5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds,compositions and methods of use thereof

ABSTRACT

Compounds of Formula (00A) and methods of use as Janus kinase inhibitors are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/139,164, filed Apr. 26, 2016, which is a continuation of U.S.application Ser. No. 14/720,323, filed May 22, 2015, which claims thebenefit of: U.S. Provisional Application No. 62/130,098, filed Mar. 9,2015; U.S. Provisional Application No. 62/101,234, filed Jan. 8, 2015;U.S. Provisional Application No. 62/002,547, filed May 23, 2014; andInternational Application No. PCT/CN2015/077176, filed Apr. 22, 2015,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The field of the invention pertains to compounds of Formula (00A), andsubformulas thereof, which are inhibitors of a Janus kinase, such asJAK1, as well as compositions containing these compounds, and methods ofuse including, but not limited to, diagnosis or treatment of patientssuffering from a condition responsive to the inhibition of a JAK kinase.

BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions,including many aspects of inflammation and immunity. Janus kinases(JAK), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic proteinkinases that associate with type I and type II cytokine receptors andregulate cytokine signal transduction. Cytokine engagement with cognatereceptors triggers activation of receptor associated JAKs and this leadsto JAK-mediated tyrosine phosphorylation of signal transducer andactivator of transcription (STAT) proteins and ultimatelytranscriptional activation of specific gene sets (Schindler et al.,2007, J. Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broadpatterns of gene expression, while JAK3 expression is limited toleukocytes. Cytokine receptors are typically functional as heterodimers,and as a result, more than one type of JAK kinase is usually associatedwith cytokine receptor complexes. The specific JAKs associated withdifferent cytokine receptor complexes have been determined in many casesthrough genetic studies and corroborated by other experimental evidence.Exemplary therapeutic benefits of the inhibition of JAK enzymes arediscussed, for example, in International Application No. WO 2013/014567.

JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic andbiochemical studies have shown that JAK1 is functionally and physicallyassociated with the type I interferon (e.g., IFNalpha), type IIinterferon (e.g., IFNgamma), and IL-2 and IL-6 cytokine receptorcomplexes (Kisseleva et al., 2002, Gene 285:1-24; Levy et al., 2005,Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). JAK1 knockout mice die perinatally due to defectsin LIF receptor signaling (Kisseleva et al., 2002, Gene 285:1-24; O'Sheaet al., 2002, Cell, 109 (suppl.): S121-S131). Characterization oftissues derived from JAK1 knockout mice demonstrated critical roles forthis kinase in the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) wasapproved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009, Nat.Rev. Drug Discov. 8:273-274).

CD4 T cells play an important role in asthma pathogenesis through theproduction of TH2 cytokines within the lung, including IL-4, IL-9 andIL-13 (Cohn et al., 2004, Annu. Rev. Immunol. 22:789-815). IL-4 andIL-13 induce increased mucus production, recruitment of eosinophils tothe lung, and increased production of IgE (Kasaian et al., 2008,Biochem. Pharmacol. 76(2): 147-155). IL-9 leads to mast cell activation,which exacerbates the asthma symptoms (Kearley et al., 2011, Am. J.Resp. Crit. Care Med., 183(7): 865-875). The IL-4Rα chain activates JAK1and binds to either IL-4 or IL-13 when combined with the common gammachain or the IL-13Rα1 chain respectively (Pernis et al., 2002, J. Clin.Invest. 109(10):1279-1283). The common gamma chain can also combine withIL-9Rα to bind to IL-9, and IL-9Rα activates JAK1 as well (Demoulin etal., 1996, Mol. Cell Biol. 16(9):4710-4716). While the common gammachain activates JAK3, it has been shown that JAK1 is dominant over JAK3,and inhibition of JAK1 is sufficient to inactivate signaling through thecommon gamma chain despite JAK3 activity (Haan et al., 2011, Chem. Biol.18(3):314-323). Inhibition of IL-4, IL-13 and IL-9 signaling by blockingthe JAK/STAT signaling pathway can alleviate asthmatic symptoms inpre-clinical lung inflammation models (Mathew et al., 2001, J. Exp. Med.193(9): 1087-1096; Kudlacz et. al., 2008, Eur. J. Pharmacol. 582(1-3):154-161).

Biochemical and genetic studies have shown an association between JAK2and single-chain (e.g., EPO), IL-3 and interferon gamma cytokinereceptor families (Kisseleva et al., 2002, Gene 285:1-24; Levy et al.,2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell,109 (suppl.): S121-S131). Consistent with this, JAK2 knockout mice dieof anemia (O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Kinaseactivating mutations in JAK2 (e.g., JAK2 V617F) are associated withmyeloproliferative disorders in humans.

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID) (O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3and JAK3-mediated pathways have been targeted for immunosuppressiveindications (e.g., transplantation rejection and rheumatoid arthritis)(Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelianet al., 2003, Science 302: 875-878).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al.,2002, Gene 285:1-24; Watford, W. T. & O'Shea, J. J., 2006, Immunity25:695-697). Consistent with this, primary cells derived from a TYK2deficient human are defective in type I interferon, IL-6, IL-10, IL-12and IL-23 signaling. A fully human monoclonal antibody targeting theshared p40 subunit of the IL-12 and IL-23 cytokines (Ustekinumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe plaque psoriasis (Krueger et al., 2007, N. Engl. J.Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356).In addition, an antibody targeting the IL-12 and IL-23 pathwaysunderwent clinical trials for treating Crohn's Disease (Mannon et al.,2004, N. Engl. J. Med. 351:2069-79).

There exists a need in the art for additional or alternative treatmentsof conditions mediated by JAK kinases, such as those described above.

SUMMARY OF INVENTION

Provided herein are 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidinecompounds that inhibit one or more JAK kinases.

Accordingly, one aspect of the invention includes a compound of Formula(00A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₄ alkenyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either ofX^(A) and X^(B) are independently C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₅alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 memberedheterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 memberedheteroaryl, each of X^(A) and X^(B) is independently optionallysubstituted by Y¹, wherein Y¹ is selected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11        membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C₁-C₆        alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C₁-C₆ alkyl),        —S—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b),        —N(+)R^(a)R^(b)R^(c) wherein R^(c) is methyl, —C(O)NR^(a)R^(b),        −(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and        phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, heteroaryl, and phenyl of T¹ is optionally        substituted by OH, —C(O)O—(C₁-C₆ alkyl), C₁-C₆ alkyl, halo, CN,        oxo, —(C₁-C₆ alkyl)CONR^(a)R^(b), —NR^(a)R^(b), phenyl, or        —O—(C₁-C₆ alkyl) optionally substituted by OH;    -   (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl; wherein the        heterocycloalkyl is optionally substituted by OH, halo, CN,        C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl),        —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —(C₁-C₆        alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)Rb;    -   (c) N(+)(AA)₃, wherein each AA is independently C₁-C₆ alkyl        optionally substituted by phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        NR^(a)R^(b), or CN;    -   (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)OH, —C(O)O—(C₁-C₆        alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), or        —C(O)-4-6 membered heterocycloalkyl optionally substituted by        —(C₁-C₆ alkyl) or —NR^(a)R^(b), or —C(O)O—(C₁-C₆ alkyl)        optionally substituted by OH, NR^(a)R^(b), or 3-11 membered        heterocycloalkyl wherein said heterocycloalkyl is optionally        substituted by C₁-C₆ alkyl;    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, CN, or 3-11 membered heterocycloalkyl        optionally substituted by C₁-C₆ alkyl or 3-11 membered        heterocycloalkyl;    -   (j) isoindolin-2-yl optionally substituted by halo;    -   (k) —NR^(a)R^(b), and    -   (l) —O—CH₂C(O)-3-11 membered heterocycloalkyl;    -   wherein R^(a) and R^(b) are independently selected from:        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O—(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, —NR^(az)R^(bz),            —C(O)NR^(az)Rb^(bz), oxo, —O—(C₁-C₆ alkyl), 5-6 membered            heteroaryl optionally substituted by C₁-C₆ alkyl or halo, or            benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl            optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   wherein R^(az) and R^(bz) are each independently selected from        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O—(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6            membered heteroaryl optionally substituted by C₁-C₆ alkyl or            halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered            heterocycloalkenyl optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,            with the following provisos: when R⁰, R⁰⁰, and R¹ are each H            and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and t¹is 0, then X^(A) cannot be —NR^(a)R^(b).

Further, another aspect of the invention includes a compound of Formula(00A), further defined as a compound of Formula (0A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₄ alkenyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either ofX^(A) and X^(B) are independently C₁-C₆ alkyl, C₂-C₅ alkynyl,3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 memberedheterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 memberedheteroaryl, each of X^(A) and X^(B) are independently optionallysubstituted by Y¹, wherein Y¹ is selected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11        membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C₁-C₆        alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C₁-C₆ alkyl),        —S—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b),        —N(+)R^(a)R^(b)R^(c) wherein R^(c) is methyl, —C(O)NR^(a)R^(b),        —(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and        phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, heteroaryl, and phenyl of T¹ is optionally        substituted by OH, —C(O)O—(C₁-C₆ alkyl), C₁-C₆ alkyl, halo, CN,        oxo, —NR^(a)R^(b), phenyl, or —O—(C₁-C₆ alkyl) optionally        substituted by OH;    -   (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl; wherein the        heterocycloalkyl is optionally substituted by OH, halo, CN,        C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl),        —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —(C₁-C₆        alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)R^(b); (c) N(+)(AA)₃, wherein        each AA is independently C₁-C₆ alkyl optionally substituted by        phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        or CN; (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)OH, —C(O)O—(C₁-C₆        alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), or        —C(O)-4-6 membered heterocycloalkyl optionally substituted by        —NR^(a)R^(b), or —C(O)O—(C₁-C₆ alkyl) optionally substituted by        OH, NR^(a)R^(b), or 3-11 membered heterocycloalkyl wherein said        heterocycloalkyl is optionally substituted by C1-C6 alkyl;    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, or CN;    -   (j) isoindolin-2-yl optionally substituted by halo; and    -   (k) —NR^(a)R^(b),    -   wherein R^(a) and R^(b) are independently selected from:        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O—(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, —NR^(az)R^(bz),            —C(O)NR^(az)R^(bz), oxo, —O—(C₁-C₆ alkyl), 5-6 membered            heteroaryl optionally substituted by C₁-C₆ alkyl or halo, or            benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl            optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) 3-6 membered cycloalkyl optionally substituted by OH,            halo, CN, or C₁-C₆ alkyl optionally substituted by OH;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   wherein R^(az) and R^(bz) are each independently selected from        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O—(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6            membered heteroaryl optionally substituted by C₁-C₆ alkyl or            halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered            heterocycloalkenyl optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,            with the following provisos: when R⁰, R⁰⁰, and R¹ are each H            and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and t¹is 0, then X^(A) cannot be —NR^(a)R^(b).

Another aspect of the invention includes a compound of Formula (00A),further defined as a compound of Formula (A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,—NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl, 6-10 memberedaryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl,and 5-10 membered heteroaryl; wherein when either of X^(A) and X^(B) areindependently C₁-C₆ alkyl, C₂-C₅ alkynyl, 3-6-membered cycloalkyl, 6-10membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl, each of X^(A) andX^(B) are independently optionally substituted by Y¹, wherein Y¹ isselected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, —O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl),        —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b), —N(+)R^(a)R^(b)R^(c) wherein        R^(c) is methyl, —C(O)NR^(a)R^(b), —(2-oxoindolin-1-yl),        —OC(O)-3-6 membered cycloalkyl, and phenyl, wherein each alkyl,        cycloalkyl, and phenyl of T¹ is optionally substituted by OH,        C₁—C₆ alkyl, halo, CN, oxo, —NR^(a)R^(b), phenyl, or —O—(C₁-C₆        alkyl) optionally substituted by OH;        (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl; wherein the        heterocycloalkyl is optionally substituted by OH, halo, CN,        C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl),        —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —(C₁-C₆        alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)R^(b);    -   (c) N(+)(AA)₃, wherein each AA is independently C₁-C₆ alkyl        optionally substituted by phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        or CN;    -   (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl) optionally        substituted by OH, —C(O)OH, —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), or —C(O)-4-6 membered        heterocycloalkyl optionally substituted by —NR^(a)R^(b),    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, or CN;    -   (j) isoindolin-2-yl optionally substituted by halo; and    -   (k) —NR^(a)R^(b),    -   wherein R^(a) and R^(b) are independently selected from:        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            naphthylenyl, —NR^(az)R^(bz), —C(O)NR^(az)R^(bz), oxo,            —O—(C₁-C₆ alkyl), phenyl, 5-6 membered heteroaryl optionally            substituted by C₁-C₆ alkyl or halo, or            benzo[1,3]dioxol-2-yl;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), or            —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo or            C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) 3-6 membered cycloalkyl optionally substituted by OH,            halo, CN, or C₁-C₆ alkyl optionally substituted by OH;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   wherein R^(az) and R^(bz) are each independently selected from        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6            membered heteroaryl optionally substituted by C₁-C₆ alkyl or            halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered            heterocycloalkenyl optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   with the following provisos: when R⁰, R⁰⁰, and R⁰¹ are each H        and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and t¹is 0, then X^(A) cannot be —NR^(a)R^(b).

Also provided are pharmaceutical compositions comprising a5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine as described herein,such as a compound of Formula (00A) and a pharmaceutically acceptablecarrier, dilient or excipient.

The present invention also provides, in some embodiments, use of a5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), in therapy, suchas in the treatment of an inflammatory disease. Also provided are usesof a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), for thepreparation of a medicament for the treatment of an inflammatorydisease. Also provided is a method of preventing, treating or lesseningthe severity of a disease or condition responsive to the inhibition of aJanus kinase activity in a patient, comprising administering to thepatient a therapeutically effective amount of a5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A).

DESCRIPTION OF THE DRAWINGS

The foregoing aspects and many of the attendant advantages will becomemore readily appreciated as the same become better understood byreference to the following detailed description, when taken inconjunction with the accompanying drawings, where:

FIG. 1 depicts a matched pair analysis of certain compounds of thepresent invention containing either an OMe (i) or OCHF₂ (ii) group atthe indicated position.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms suchas “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted. In one example, the alkyl radical is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical isC₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C1-C₅, C₁-C₄, orC₁-C₃. Co alkyl refers to a bond. Examples of alkyl groups includemethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)2), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)2CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)2),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. In someembodiments, substituents for “optionally substituted alkyls” includeone to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂,NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl,butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein thealkyl, phenyl and heterocyclic portions thereof may be optionallysubstituted, such as by one to four instances of substituents selectedfrom this same list.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon double bond, wherein the alkenyl radical may be optionallysubstituted, and includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl(—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl. In some embodiments,substituents for “optionally substituted alkenyls” include one to fourinstances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃,C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl,isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon,triple bond, wherein the alkynyl radical may be optionally substituted.In one example, the alkynyl radical is two to eighteen carbon atoms(C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀,C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethynyl(—C—CH), prop-1-ynyl (—C—CCH₃), prop-2-ynyl (propargyl, —CH₂C—CH),but-1-ynyl, but-2-ynyl and but-3-ynyl. In some embodiments, substituentsfor “optionally substituted alkynyls” include one to four instances ofF, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list.

“Alkylene” refers to a saturated, branched or straight chain hydrocarbongroup having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. In one example, the divalent alkylene group is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the divalent alkylenegroup is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅,C₁-C₄, or C₁-C₃. The group C₀ alkylene refers to a bond. Examplealkylene groups include methylene (—CH₂—), 1,1-ethyl (—CH(CH₃)—),(1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—), 2,2-propyl(—C(CH₃)₂—), 1,2-propyl (—CH(CH₃)CH₂—), 1,3-propyl (—CH₂CH₂CH₂—),1,1-dimethyleth-1,2-yl (—C(CH₃)₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

The term “heteroalkyl” refers to a straight or branched chain monovalenthydrocarbon radical, consisting of the stated number of carbon atoms,or, if none are stated, up to 18 carbon atoms, and from one to fiveheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms can optionally be oxidized and thenitrogen heteroatom can optionally be quaternized. In some embodiments,the heteroatom is selected from O, N and S, wherein the nitrogen andsulfur atoms can optionally be oxidized and the nitrogen heteroatom canoptionally be quaternized. The heteroatom(s) can be placed at anyinterior position of the heteroalkyl group, including the position atwhich the alkyl group is attached to the remainder of the molecule(e.g., —O—CH₂—CH₃). Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃,—Si(CH₃)₃ and —CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive,such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Heteroalkylgroups can be optionally substituted.

In some embodiments, substituents for “optionally substitutedheteroalkyls” include one to four instances of F, Cl, Br, I, OH, SH, CN,NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl,propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy,propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list.

“Amino” means primary (i.e., —NH₂), secondary (i.e., —NRH), tertiary(i.e., —NRR) and quaternary (i.e., —N(+)RRR) amines, that are optionallysubstituted, in which each R is the same or different and selected fromalkyl, cycloalkyl, aryl, and heterocyclyl, wherein the alkyl,cycloalkyl, aryl and heterocyclyl groups are as defined herein.Particular secondary and tertiary amines are alkylamine, dialkylamine,arylamine, diarylamine, aralkylamine and diaralkylamine, wherein thealkyl and aryl portions can be optionally substituted. Particularsecondary and tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine,dipropylamine and diisopropylamine. In some embodiments, R groups of aquarternary amine are each independently optionally substituted alkylgroups.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused toone or more groups, having the number of carbon atoms designated, or ifno number is designated, up to 14 carbon atoms. One example includesaryl groups having 6-14 carbon atoms. Another example includes arylgroups having 6-10 carbon atoms. Examples of aryl groups include phenyl,naphthyl, biphenyl, phenanthrenyl, naphthacenyl,1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, andthe like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.)13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substitutedphenyl or substituted aryl means a phenyl group or aryl groupsubstituted with one, two, three, four or five substituents, forexample, 1-2, 1-3 or 1-4 substituents, such as chosen from groupsspecified herein (see “optionally substituted” definition), such as F,Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list. Examples of theterm “substituted phenyl” include a mono- or di(halo)phenyl group suchas 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group suchas 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methyl sulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl” representsdisubstituted phenyl groups where the substituents are different, forexample, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl,3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl,2-chloro-5-difluoromethoxy and the like, as well as trisubstitutedphenyl groups where the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. In someembodiments, a substituent of an aryl, such as phenyl, comprises anamide. For example, an aryl (e.g., phenyl) substituent may be—(CH₂)₀₋₄CONR′R″, wherein R′ and R″ each independently refer to groupsincluding, for example, hydrogen; unsubstituted C₁-C₆ alkyl; C₁-C₆ alkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆ heteroalkyl; C₁-C₆heteroalkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆C₁₀ aryl;C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); and 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; or R′ and R″ can be combined with the nitrogen atom toform a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom isoptionally substituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

-   -   “Cycloalkyl” refers to a non-aromatic, saturated or partially        unsaturated hydrocarbon ring group wherein the cycloalkyl group        may be optionally substituted independently with one or more        substituents described herein. In one example, the cycloalkyl        group is 3 to 12 carbon atoms (C₃-C₁₂). In other examples,        cycloalkyl is C₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other examples, the        cycloalkyl group, as a monocycle, is C₃-C₈, C₃-C₆ or C₅-C₆. In        another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂.        In another example, the cycloalkyl group, as a spiro system, is        C₅-C₁₂. Examples of monocyclic cycloalkyl include cyclopropyl,        cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,        1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl,        1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,        cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,        cyclodecyl, cycloundecyl and cyclododecyl. Exemplary        arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms        include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or        [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls        include, but are not limited to, bicyclo[2.2.1]heptane,        bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.

Examples of spiro cycloalkyl include, spiro[2.2]pentane,spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane andspiro[4.5]decane. In some embodiments, substituents for “optionallysubstituted cycloalkyls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonyl amino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list. In some embodiments, asubstituent of a cycloalkyl comprises an amide. For example, acycloalkyl substituent may be —(CH₂)₀₋₄CONR′R″, wherein R′ and R″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆ alkyl; C₁-C₆ alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; or R′ and R″ can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring wherein a ring atom is optionally substituted with N, O or S andwherein the ring is optionally substituted with halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.“Guanidine” or “guanidinyl” means the group —NH—C(NH)—NHR in which R ishydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl,cycloalkyl, aryl and heterocyclyl groups are as defined herein. Aparticular guanidine is the group —NH—C(NH)—NH₂.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” are used interchangeably and refer to any mono-, bi-,tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) ornon-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ringatoms, where the ring atoms are carbon, and at least one atom in thering or ring system is a heteroatom selected from nitrogen, sulfur oroxygen. If any ring atom of a cyclic system is a heteroatom, that systemis a heterocycle, regardless of the point of attachment of the cyclicsystem to the rest of the molecule. In one example, heterocyclylincludes 3-11 ring atoms (“members”) and includes monocycles, bicycles,tricycles and spiro ring systems, wherein the ring atoms are carbon,where at least one atom in the ring or ring system is a heteroatomselected from nitrogen, sulfur or oxygen. In one example, heterocyclylincludes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to3 heteroatoms. In another example, heterocyclyl includes 3- to7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selectedfrom nitrogen, sulfur or oxygen. In another example, heterocyclylincludes 3-membered monocycles. In another example, heterocyclylincludes 4-membered monocycles. In another example, heterocyclylincludes 5-6 membered monocycles, e.g., 5-6 membered heteroaryl. Inanother example, heterocyclyl includes 3-11 membered heterocycloyalkyls,such as 4-11 membered heterocycloalkyls. In some embodiments, aheterocycloalkyl includes at least one nitrogen. In one example, theheterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfurheteroatom may optionally be oxidized (e.g., NO, SO, SO₂), and anynitrogen heteroatom may optionally be quaternized (e.g., [NR₄]⁺Cl⁻,[NR₄]⁺OH⁻). Example heterocycles are oxiranyl, aziridinyl, thiiranyl,azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl,pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl,dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl,piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl,thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclescontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocycles containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocycles contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocycle groups.Heterocycles may be optionally substituted. For example, substituentsfor “optionally substituted heterocycles” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonyl amino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list. Insome embodiments, a substituent of a heterocyclic group, such as aheteroaryl or heterocycloalkyl, comprises an amide. For example, aheterocyclic (e.g., heteroaryl or heterocycloalkyl) substituent may be—(CH₂)₀₋₄CONR′R″, wherein R′ and R″ each independently refer to groupsincluding, for example, hydrogen; unsubstituted C₁-C₆ alkyl; C₁-C₆ alkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆ heteroalkyl; C₁-C₆heteroalkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl;C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); and 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; or R′ and R″ can be combined with the nitrogen atom toform a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom isoptionally substituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where atleast one ring is a 5- or 6-membered aromatic ring containing from 1 to4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in anexample embodiment, at least one heteroatom is nitrogen. See, forexample, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed.Table 7-2 [1985]. Included in the definition are any bicyclic groupswhere any of the above heteroaryl rings are fused to an aryl ring,wherein the aryl ring or the heteroaryl ring is joined to the remainderof the molecule. In one embodiment, heteroaryl includes 5-6 memberedmonocyclic aromatic groups where one or more ring atoms is nitrogen,sulfur or oxygen. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. Heteroaryl groups can be optionallysubstituted. In some embodiments, substituents for “optionallysubstituted heteroaryls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list. In some embodiments, asubstituent of a heteroaryl comprises an amide. For example, aheteroaryl substituent may be —(CH₂)₀₋₄CONR′R″, wherein R′ and R″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆ alkyl; C₁-C₆ alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; or R′ and R″ can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring wherein a ring atom is optionally substituted with N, O or S andwherein the ring is optionally substituted with halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

In particular embodiments, a heterocyclyl group is attached at a carbonatom of the heterocyclyl group. By way of example, carbon bondedheterocyclyl groups include bonding arrangements at position 2, 3, 4, 5,or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring,position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of apyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4,or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 ofan isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of anaziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3,4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way ofexample, nitrogen bonded heterocyclyl or heteroaryl groups includebonding arrangements at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of a isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, as defined herein.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di-and tri-fluoromethoxy and cyclopropoxy.

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl, wherein the alkyl, cycloalkyl, aryl and heterocyclyl areas defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl(e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4,or 5 or more, or any range derivable therein) of the substituents listedfor that group in which said substituents may be the same or different.In an embodiment, an optionally substituted group has 1 substituent. Inanother embodiment an optionally substituted group has 2 substituents.In another embodiment an optionally substituted group has 3substituents. In another embodiment an optionally substituted group has4 substituents. In another embodiment an optionally substituted grouphas 5 substituents.

Optional substituents for alkyl radicals, alone or as part of anothersubstituent (e.g., alkoxy), as well as alkylenyl, alkenyl, alkynyl,heteroalkyl, heterocycloalkyl, and cycloalkyl, also each alone or aspart of another substituent, can be a variety of groups, such as thosedescribed herein, as well as selected from the group consisting ofhalogen; oxo; CN; NO; N₃; —OR′; perfluoro-C₁-C₄ alkoxy; unsubstitutedC₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl (e.g., phenyl); C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; —NR′R″; —SR′;—SiR′R″R′″; —OC(O)R′; —C(O)R′; —CO₂R′; —CONR′R″; —OC(O)NR′R″;—NR″C(O)R′″; —NR′″C(O)NR′R″; —NR″C(O)₂R′; —S(O)₂R′; —S(O)₂NR′R″;—NR′S(O)₂R″; —NR′″S(O)₂NR′R″; amidinyl; guanidinyl; —(CH₂)₁₋₄—OR′;—(CH₂)₁₋₄—NR′R″; —(CH₂)₁₋₄—SR′; —(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′;—(CH₂)₁₋₄—C(O)R′; —(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinationsthereof, in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆ alkyl; C₁-C₆ alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein aring atom is optionally substituted with N, O or S and wherein the ringis optionally substituted with halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. For example, —NR′R″ ismeant to include 1-pyrrolidinyl and 4-morpholinyl.

Similarly, optional substituents for the aryl and heteroaryl groups arevaried. In some embodiments, substituents for aryl and heteroaryl groupsare selected from the group consisting of halogen; CN; NO; N₃; —OR′;perfluoro-C₁-C₄ alkoxy; unsubstituted C₃-C₇ cycloalkyl; C₃-C₇ cycloalkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl (e.g., phenyl);C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; —NR′R″; —SR′; —SiR′R″R′″; —OC(O)R′; —C(O)R′; —CO₂R′;—CONR′R″; —OC(O)NR′R″; —NR″C(O)R′; —NR′″C(O)NR′R″; —NR″C(O)₂R′;—S(O)₂R′; —S(O)₂NR′R″; —NR′S(O)₂R″; —NR′″S(O)₂NR′R″; amidinyl;guanidinyl; —(CH₂)₁₋₄—OR′; —(CH₂)₁₋₄—NR′R″; —(CH₂)₁₋₄—SR′;—(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′; —(CH₂)₁₋₄—C(O)R′;—(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinations thereof, in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical. R′, R″ and R′″ each independently refer togroups including, for example, hydrogen; unsubstituted C₁-C₆ alkyl;C₁-C₆ alkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆heteroalkyl; C₁-C₆ heteroalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, or NR′R″;unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS); and 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionallysubstituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. For example, —NR′R″ is meantto include 1-pyrrolidinyl and 4-morpholinyl.

The term “oxo” refers to ═O or (═O)₂.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule. In some embodiments, an arrow together withan asterisk is used in the manner of a wavy line to indicate a point ofattachment.

In certain embodiments, divalent groups are described genericallywithout specific bonding configurations. It is understood that thegeneric description is meant to include both bonding configurations,unless specified otherwise. For example, in the group R¹—R²—R³, if thegroup R² is described as —CH₂C(O)—, then it is understood that thisgroup can be bonded both as R¹—CH₂C(O)—R³, and as R¹—C(O)CH₂—R³, unlessspecified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, such as, for example,a human, as appropriate.

Compounds of the present invention may be in the form of a salt, such asa pharmaceutically acceptable salt. “Pharmaceutically acceptable salts”include both acid and base addition salts. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particular base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases include isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride,hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate,maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate,ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate,saccharinate, adipate, formate, glycolate, palmitate, L-lactate,D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate(e.g., 2-furoate or 3-furoate), napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), 2-mesitylenesulphonate,2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate,L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate(2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate(camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acidsalt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate),orotate, xylate (p-xylene-2-sulphonate), and pamoic(2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all livingmicroorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include diastereomers, enantiomers,conformers and the like.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. Mixturesof diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and 1 or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or 1 meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. A “solvate” refersto an association or complex of one or more solvent molecules and acompound of the present invention. Examples of solvents that formsolvates include water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine. Certain compounds of the presentinvention can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are intended to be within the scope of thepresent invention. The term “hydrate” refers to the complex where thesolvent molecule is water.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. Such products can result,for example, from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, and imines, as well as many N-heteroatom derivatives whichcan be removed to regenerate the desired amine group. Particular aminoprotecting groups are Pmb (p-Methoxybenzyl), Boc(tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyl oxycarbonyl) and Cbz(Carbobenzyloxy). Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups thatare stable to the conditions of subsequent reaction(s) at otherpositions of the molecule, which may be removed at the appropriate pointwithout disrupting the remainder of the molecule, to give theunprotected carboxy-group. Examples of carboxy protecting groupsinclude, ester groups and heterocyclyl groups. Ester derivatives of thecarboxylic acid group may be employed to block or protect the carboxylicacid group while reactions are carried out on other functional groups onthe compound. Examples of such ester groups include substitutedarylalkyl, including substituted benzyls, such as 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, alkyl or substituted alkyl esters suchas methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl),4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl,2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esterssuch as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl,2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzyl sulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Anotherexample of carboxy-protecting groups are heterocyclyl groups such as1,3-oxazolinyl. Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected carboxy”refers to a carboxy group substituted with one of the abovecarboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g., TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protecting Groups inOrganic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term“protected hydroxy” refers to a hydroxy group substituted with one ofthe above hydroxy-protecting groups.

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. Mammals include, but are notlimited to, farm animals (such as cows), sport animals, pets (such asguinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.In certain embodiments, a mammal is a human. In embodiments comprisingadministration of a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, to a patient, the patient is typicallyin need thereof.

The term “Janus kinase” refers to JAK1, JAK2, JAK3 and TYK2 proteinkinases. In some embodiments, a Janus kinase may be further defined asone of JAK1, JAK2, JAK3 or TYK2. In any embodiment, any one of JAK1,JAK2, JAK3 and TYK2 may be specifically excluded as a Janus kinase. Insome embodiments, a Janus kinase is JAK1. In some embodiments, a Januskinase is a combination of JAK1 and JAK2.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., JAK1 activity)compared to normal.

In some embodiments, a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, is selective for inhibition of JAK1over JAK3 and TYK2. In some embodiments, a compound of Formula (00A),(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X), or a compound of Table 1 or of Examples 1-468, isselective for inhibition of JAK1 over JAK2, JAK3, or TYK2, or anycombination of JAK2, JAK3, or TYK2. In some embodiments, a compound ofFormula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or a compound of Table 1 or of Examples1-468, is selective for inhibition of JAK1 and JAK2 over JAK3 and TYK2.In some embodiments, a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, is selective for inhibition of JAK1over JAK3. By “selective for inhibition” it is meant that the compoundis at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivabletherein, better inhibitor of a particular Janus kinase (e.g., JAK1)activity compared to another particular Janus kinase (e.g., JAK1)activity, or is at least a 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or500-fold better inhibitor of a particular Janus kinase (e.g., JAK1)activity compared to another particular Janus kinase (e.g., JAK1)activity.

“Therapeutically effective amount” means an amount of a compound of thepresent invention, such as a compound of Formula (00A), (0A), (A), (Ia),(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or acompound of Table 1 or of Examples 1-468, that (i) treats or preventsthe particular disease, condition or disorder, or (ii) attenuates,ameliorates or eliminates one or more symptoms of the particulardisease, condition, or disorder, and optionally (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, conditionor disorder described herein. In some embodiments, the therapeuticallyeffective amount is an amount sufficient to decrease or alleviate thesymptoms of an autoimmune or inflammatory disease (e.g., asthma). Insome embodiments, a therapeutically effective amount is an amount of achemical entity described herein sufficient to significantly decreasethe activity or number of B-cells. In the case of cancer, thetherapeutically effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; or relieve to someextent one or more of the symptoms associated with the cancer. To theextent the drug may prevent growth or kill existing cancer cells, it maybe cytostatic or cytotoxic. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)or determining the response rate (RR).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, compounds of the invention,such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1or of Examples 1-468, are used to delay development of a disease ordisorder or to slow the progression of a disease or disorder. Those inneed of treatment include those already with the condition or disorderas well as those prone to have the condition or disorder, (for example,through a genetic mutation) or those in which the condition or disorderis to be prevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome inwhich an excessive or unregulated inflammatory response leads toexcessive inflammatory symptoms, host tissue damage, or loss of tissuefunction. “Inflammatory disorder” also refers to a pathological statemediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute, orwall off (sequester) both the injurious agent and the injured tissue.Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with a compound of thepresent invention, such as a compound of Formula (00A), (0A), (A), (Ia),(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or acompound of Table 1 or of Examples 1-468, encompass disorders associatedwith reactions of the specific defense system as well as with reactionsof the nonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity responses mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” refers to inflammatory disordersthat are mediated by leukocytes that are incapable of immunologicalmemory (e.g., granulocytes, and macrophages). Examples of inflammationthat result, at least in part, from a reaction of the nonspecificdefense system include inflammation associated with conditions such asadult (acute) respiratory distress syndrome (ARDS) or multiple organinjury syndromes; reperfusion injury; acute glomerulonephritis; reactivearthritis; dermatoses with acute inflammatory components; acute purulentmeningitis or other central nervous system inflammatory disorders suchas stroke; thermal injury; inflammatory bowel disease; granulocytetransfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissueinjury is associated with humoral or cell-mediated responses to thebody's own constituents. Non-limiting examples of autoimmune diseasesinclude rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treatedaccording to the methods of this invention include, but are not limitedto, asthma, rhinitis (e.g., allergic rhinitis), allergic airwaysyndrome, atopic dermatitis, bronchitis, rheumatoid arthritis,psoriasis, contact dermatitis, chronic obstructive pulmonary disease anddelayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and relatedterms refer to or describe the physiological condition in mammals thatis typically characterized by unregulated cell growth. A “tumor”comprises one or more cancerous cells. Examples of cancer includecarcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma,leukemia, and myeloid or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer) and lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung. Other cancers include skin, keratoacanthoma,follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,hepatocellular, gastric, stomach, gastrointestinal, small intestine,large intestine, pancreatic, cervical, ovarian, liver, bladder,hepatoma, breast, colon, rectal, colorectal, genitourinary, biliarypassage, thyroid, papillary, hepatic, endometrial, uterine, salivarygland, kidney or renal, prostate, testis, vulval, peritoneum, anal,penile, bone, multiple myeloma, B-cell lymphoma, central nervous system,brain, head and neck, Hodgkin's, and associated metastases. Examples ofneoplastic disorders include myeloproliferative disorders, such aspolycythemia vera, essential thrombocytosis, myelofibrosis, such asprimary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents are well-known in the art and includeexamples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. Additionally, chemotherapeutic agentsinclude pharmaceutically acceptable salts, acids or derivatives of anyof chemotherapeutic agents, as well as combinations of two or more ofthem.

“Package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products that contain informationabout the indications, usage, dosage, administration, contraindicationsor warnings concerning the use of such therapeutic products.

The terms “compound(s) of this invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or ofExamples 1-468, and stereoisomers (including atropisomers), geometricisomers, tautomers, solvates, metabolites, isotopes, salts (e.g.,pharmaceutically acceptable salts), and prodrugs thereof. In someembodiments, solvates, metabolites, isotopes or prodrugs are excluded,or any combination thereof.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention, such as a compound of Formula(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl ¹²³I, and ¹²⁵1,respectively. Isotopically-labeled compounds (e.g., those labeled with³H and ¹⁴C) can be useful in compound or substrate tissue distributionassays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can beuseful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements). In some embodiments, in compounds of Formula (00A), (0A),(A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or(X), or a compound of Table 1 or of Examples 1-468, one or more hydrogenatoms are replaced by ²H or ³H, or one or more carbon atoms are replacedby ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by following procedures analogous tothose disclosed in the Schemes or in the Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention.

Furthermore, any compound or composition of the invention may be used inany method of the invention, and any method of the invention may be usedto produce or to utilize any compound or composition of the invention.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternative are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

Inhibitors of Janus Kinases Accordingly, one aspect of the inventionincludes a compound of Formula (00A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₄ alkenyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either ofX^(A) and X^(B) are independently C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₅alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 memberedheterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 memberedheteroaryl, each of X^(A) and X^(B) is independently optionallysubstituted by Y¹, wherein Y¹ is selected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11        membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C₁-C₆        alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C₁-C₆ alkyl),        —S—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b),        —N(+)R^(a)R^(b)R^(c) wherein R^(c) is methyl, —C(O)NR^(a)R^(b),        −(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and        phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, heteroaryl, and phenyl of T¹ is optionally        substituted by OH, —C(O)O—(C₁-C₆ alkyl), C₁-C₆ alkyl, halo, CN,        oxo, —(C₁-C₆ alkyl)CONR^(a)R^(b), —NR^(a)R^(b), phenyl, or        —O—(C₁-C₆ alkyl) optionally substituted by OH;    -   (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl; wherein the        heterocycloalkyl is optionally substituted by OH, halo, CN,        C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl),        —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —(C₁-C₆        alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)R^(b);    -   (c) N(+)(AA)₃, wherein each AA is independently C₁-C₆ alkyl        optionally substituted by phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        NR^(a)R^(b), or CN;    -   (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)OH, —C(O)O—(C₁-C₆        alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), or        —C(O)-4-6 membered heterocycloalkyl optionally substituted by        —(C₁-C₆ alkyl) or —NR^(a)R^(b), or —C(O)O—(C₁-C₆ alkyl)        optionally substituted by OH, NR^(a)R^(b), or 3-11 membered        heterocycloalkyl wherein said heterocycloalkyl is optionally        substituted by C₁-C₆ alkyl;    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, CN, or 3-11 membered heterocycloalkyl        optinally substituted by C₁-C₆ alkyl or 3-11 membered        heterocycloalkyl;    -   (j) isoindolin-2-yl optionally substituted by halo;    -   (k) —NR^(a)R^(b), and    -   (l) —O—CH₂C(O)-3-11 membered heterocycloalkyl;    -   wherein R^(a) and R^(b) are independently selected from:        -   (p) H,        -   (a) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, —NR^(az)R^(bz),            —C(O)NR^(az)R^(bz), oxo, —O—(C₁-C₆ alkyl), 5-6 membered            heteroaryl optionally substituted by C₁-C₆ alkyl or halo, or            benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl            optionally substituted by oxo;        -   (b) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (c) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (d) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (e) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (f) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (g) C₂-C₅ alkenyl;        -   (h) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (i) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (j) phenyl,        -   (k) —C(O)(C₁-C₆ alkyl),        -   (l) —C(O)O(C₁-C₆ alkyl),        -   (m) —C(O)O(3-6 membered cycloalkyl), and        -   (n) —C(O)-phenyl,    -   wherein R^(az) and R^(bz) are each independently selected from        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6            membered heteroaryl optionally substituted by C₁-C₆ alkyl or            halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered            heterocycloalkenyl optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,        -   with the following provisos: when R⁰, R⁰⁰, and R¹ are each H            and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and t¹is 0, then X^(A)cannot be —NR^(a)R^(b).

Further, another aspect of the invention includes a compound of Formula(00A), further defined as a compound of Formula (0A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₄ alkenyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either ofX^(A) and X^(B) are independently C₁-C₆ alkyl, C₂-C₅ alkynyl,3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 memberedheterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 memberedheteroaryl, each of X^(A) and X^(B) are independently optionallysubstituted by Y¹, wherein Y¹ is selected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11        membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C₁-C₆        alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C₁-C₆ alkyl),        —S—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b),        —N(+)R^(a)R^(b)R^(c) wherein R^(c) is methyl, —C(O)NR^(a)R^(b),        −(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and        phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, heteroaryl, and phenyl of T¹ is optionally        substituted by OH, —C(O)O—(C₁-C₆ alkyl), C₁-C₆ alkyl, halo, CN,        oxo, —NR^(a)R^(b), phenyl, or —O—(C₁-C₆ alkyl) optionally        substituted by OH;    -   (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl; wherein the        heterocycloalkyl is optionally substituted by OH, halo, CN,        C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl),        —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkylene)-phenyl,        —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —(C₁-C₆        alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)R^(b);    -   (c) N(+)(AA)₃, wherein each AA is independently C₁-C₆ alkyl        optionally substituted by phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        or CN;    -   (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)OH, —C(O)O—(C₁-C₆        alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b), or        —C(O)-4-6 membered heterocycloalkyl optionally substituted by        —NR^(a)R^(b), or —C(O)O—(C₁-C₆ alkyl) optionally substituted by        OH, NR^(a)R^(b), or 3-11 membered heterocycloalkyl wherein said        heterocycloalkyl is optionally substituted by C₁-C₆ alkyl;    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, or CN;    -   (j) isoindolin-2-yl optionally substituted by halo; and    -   (k) —NR^(a)R^(b),    -   wherein R^(a) and R^(b) are independently selected from:        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, —NR^(az)R^(bz),            —C(O)NR^(az)R^(bz), oxo, —O—(C₁-C₆ alkyl), 5-6 membered            heteroaryl optionally substituted by C₁-C₆ alkyl or halo, or            benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl            optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) 3-6 membered cycloalkyl optionally substituted by OH,            halo, CN, or C₁-C₆ alkyl optionally substituted by OH;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   wherein R^(az) and R^(bz) are each independently selected from        -   (a) H,        -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,            —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered            heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),            —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6            membered heteroaryl optionally substituted by C₁-C₆ alkyl or            halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered            heterocycloalkenyl optionally substituted by oxo;        -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the            alkylene is optionally substituted by OH, halo, or CN;        -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally            substituted by halo and the phenyl is optionally substituted            by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆            alkyl, or —O-phenyl;        -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein            the heterocycloalkyl is optionally substituted by halo, oxo,            or C₁-C₆ alkyl;        -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is            optionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl;        -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally            substituted by OH, halo, CN, or C₁-C₆ alkyl optionally            substituted by OH or CN;        -   (h) C₂-C₅ alkenyl;        -   (i) 4-6 membered heterocycloalkyl optionally substituted by            halo,        -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by            hydroxymethyl,        -   (k) phenyl,        -   (l) —C(O)(C₁-C₆ alkyl),        -   (m) —C(O)O(C₁-C₆ alkyl),        -   (n) —C(O)O(3-6 membered cycloalkyl), and        -   (o) —C(O)-phenyl,    -   with the following provisos: when R⁰, R⁰⁰, and R⁰¹ are each H        and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and t¹is 0, then X^(A)cannot be —NR^(a)R^(b).

In some embodiments of any formula herein, when Ring Q is

and t¹ is 0, the pyrazole is not N-linked to a nitrogen of X^(A).

Another aspect of the invention provides compounds of Formula (00A),further defined as a compound of Formula (A):

and stereoisomers and salts thereof, wherein:

R⁰⁰ is H or CH₃;

R⁰¹ is H or NH₂;

R⁰ is H or NH₂; and

Ring Q is either (i) or (ii):

wherein:

t¹ and t² are each independently 0 or 1;

X^(A) and X^(B) are independently selected from the group consisting ofH, C₁-C₆ alkyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl;

wherein when either of X^(A) and X^(B) are independently C₁-C₆ alkyl,C₂-C₅ alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10membered heteroaryl, each of X^(A) and X^(B) are independentlyoptionally substituted by Y¹, wherein Y¹ is selected from:

-   -   (a) C₁-C₆ alkyl optionally substituted by T¹, wherein T¹ is        selected from the group consisting of OH, halo, CN, imino, 3-6        membered cycloalkyl, —O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl),        —SO₂—(C₁-C₆ alkyl), —NR^(a)R^(b), —N(+)R^(a)R^(b)R^(c) wherein        R^(c) is methyl, —C(O)NR^(a)R^(b), −(2-oxoindolin-1-yl),        —OC(O)-3-6 membered cycloalkyl, and phenyl,        -   wherein each alkyl, cycloalkyl, and phenyl of T¹ is            optionally substituted by OH, C₁-C₆ alkyl, halo, CN, oxo,            —NR^(a)R^(b), phenyl, or —O—(C₁-C₆ alkyl) optionally            substituted by OH;    -   (b) 3-11 membered heterocycloalkyl, —(C₁-C₆ alkylene)-3-11        membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl,        —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl, or        —OC(O)-4-6 membered heterocycloalkyl;        -   wherein heterocycloalkyl is optionally substituted by OH,            halo, CN, C₁-C₆ alkyl, —(C₁-C₆ alkylene)-CF₃, oxo,            —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆            alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b),            —NR^(a)R^(b), —(C₁-C₆ alkylene)-phenyl, or —C(O)-4-6            membered heterocycloalkyl optionally substituted by            —NR^(a)R^(b);    -   (c) N(+)(AA)₃, wherein each AA is independently C₁-C₆ alkyl        optionally substituted by phenyl;    -   (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,        or CN;    -   (e) CN, halo, or oxo;    -   (f) —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl) optionally        substituted by OH, —C(O)O—(C₁-C₆ alkylene)-phenyl, —SO₂—(C₁-C₆        alkyl), —C(O)NR^(a)R^(b), or —C(O)-4-6 membered heterocycloalkyl        optionally substituted by —NR^(a)R^(b),    -   (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein the alkyl is        optionally substituted by OH or —NR^(a)R^(b);    -   (h) phenyl optionally substituted by OH, halo, C₁-C₆ alkyl, CF₃,        or CN;    -   (i) 5-6 membered heteroaryl optionally substituted by OH, halo,        C₁-C₆ alkyl, CF₃, or CN;    -   (j) isoindolin-2-yl optionally substituted by halo; and    -   (k) —NR^(a)R^(b),        wherein R^(a) and R^(b) are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN,        naphthylenyl, —NR^(az)R^(bz), —C(O)NR^(az)R^(bz), oxo, —O—(C₁-C₆        alkyl), phenyl, 5-6 membered heteroaryl optionally substituted        by C₁-C₆ alkyl or halo, or benzo[1,3]dioxol-2-yl;    -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        alkylene is optionally substituted by OH, halo, or CN;    -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally        substituted by halo and the phenyl is optionally substituted by        OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), or —O-phenyl;    -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein the        heterocycloalkyl is optionally substituted by halo or C₁-C₆        alkyl;    -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is optionally        substituted by halo, C₁-C₆ alkyl, or —O-phenyl;    -   (g) 3-6 membered cycloalkyl optionally substituted by OH, halo,        CN, or C₁-C₆ alkyl optionally substituted by OH;    -   (h) C₂-C₅ alkenyl;    -   (i) 4-6 membered heterocycloalkyl optionally substituted by        halo,    -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by        hydroxymethyl,    -   (k) phenyl,    -   (l) —C(O)(C₁-C₆ alkyl),    -   (m) —C(O)O(C₁-C₆ alkyl),    -   (n) —C(O)O(3-6 membered cycloalkyl), and    -   (o) —C(O)-phenyl,        wherein R^(az) and R^(bz) are each independently selected from    -   (a) H,    -   (b) C₁-C₆ alkyl optionally substituted by OH, halo, CN, —C(O)OH,        —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11 membered heterocycloalkyl),        —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl), —S—(C₁-C₆ alkyl),        naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6 membered heteroaryl        optionally substituted by C₁-C₆ alkyl or halo, or        benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl        optionally substituted by oxo;    -   (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        alkylene is optionally substituted by OH, halo, or CN;    -   (d) —(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally        substituted by halo and the phenyl is optionally substituted by        OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆ alkyl,        or —O-phenyl;    -   (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein the        heterocycloalkyl is optionally substituted by halo, oxo, or        C₁-C₆ alkyl;    -   (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is optionally        substituted by halo, C₁-C₆ alkyl, or —O-phenyl;    -   (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyl optionally substituted        by OH, halo, CN, or C₁-C₆ alkyl optionally substituted by OH or        CN;    -   (h) C₂-C₅ alkenyl;    -   (i) 4-6 membered heterocycloalkyl optionally substituted by        halo,    -   (j) —(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by        hydroxymethyl,    -   (k) phenyl,    -   (l) —C(O)(C₁-C₆ alkyl),    -   (m) —C(O)O(C₁-C₆ alkyl),    -   (n) —C(O)O(3-6 membered cycloalkyl), and    -   (o) —C(O)-phenyl,        with the following provisos:

when R⁰, R⁰⁰, and R⁰¹ are each H and Ring Q is

then X^(A) is not methyl, 2-methylpropan-2-ol, or tetrahydropyranyl;and, in some embodiments, when Ring Q is (i) and t¹ is 0, then X^(A)cannot be —NR^(a)R^(b).

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (II):

wherein:

w is 0 or 1;

R^(0b) is H or NH₂;

R^(1b) is selected from the group consisting of

-   -   a. H,    -   b. C₁-C₆ alkyl optionally substituted by OH, halo, CN, —O—(C₁-C₆        alkyl), naphthylenyl, 5-6 membered heteroaryl, or        —C(O)NR^(v)R^(w), wherein R^(v) and R^(w) are independently H or        C₁-C₆ alkyl optionally substituted by halo,    -   c. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        cycloalkyl is optionally substituted by CN,    -   d. —(C₁-C₆ alkylene)-phenyl wherein the alkyl is optionally        substituted by halo and wherein the phenyl is optionally        substituted by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) or        —O-phenyl,    -   e. —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein the        heterocycloalkyl is optionally substituted by halo or C₁-C₆        alkyl,    -   f. —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl is optionally        substituted by halo or C₁-C₆ alkyl, or    -   g. 3-6 membered cycloalkyl;

R^(2b) is selected from the group consisting of H, C₁-C₆ alkyloptionally substituted by halo, or C₂-C₅ alkenyl;

or R^(1b) and R^(2b) together form a 3-11 membered heterocycloalkyloptionally substituted by OH;

R^(3b) is absent or methyl, wherein when R^(3b) is methyl, the nitrogento which it is attached is N+ and w is 1;

R^(4b) is a bond or C₁-C₆ alkylene;

R^(5b) is selected from the group consisting of H, OH, and phenyl; and

Ring F is a 3-7 membered heterocycloalkyl wherein p^(1b) is 0, 1 or 2and p^(2b) is 0, 1 or 2;

-   -   wherein w is equal to 1 only when R^(3b) is methyl.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (Ia) or Formula (Ib):

wherein:

R^(0a) is H or NH₂;

R^(1a) is bound to a nitrogen atom of Ring A in (Ia) or is bound to acarbon atom of Ring B in (Ib), and is selected from the group consistingof:

-   -   a. H,    -   b. C₁-C₆ alkyl optionally substituted by OH, halo, —O—(C₁-C₆        alkyl), —SO₂—(C₁-C₆ alkyl), -(2-oxoindolin-1-yl), —OC(O)-3-6        membered cycloalkyl, —OC(O)-4-6 membered heterocycloalkyl, or        phenyl;    -   c. —(C₁-C₆ alkylene)-O—(C₁-C₆ alkylene)-phenyl wherein the        phenyl is optionally substituted by halo;    -   d. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        cycloalkyl is optionally substituted by halo, OH, or CN;    -   e. —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl, wherein the        heterocycloalkyl is optionally substituted by oxo, C₁-C₆ alkyl,        —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl),        —C(O)-4-6 membered heterocycloalkyl, or —C(O)N(C₁-C₆        alkyl)(C₁-C₆ alkyl);    -   f. 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl        is optionally substituted by oxo, C₁-C₆ alkyl, —C(O)—(C₁-C₆        alkyl), —C(O)O—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl), —C(O)-4-6        membered heterocycloalkyl, or —C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl);    -   g. —C(O)O—(C₁-C₆ alkylene)-OH; and    -   h. —C(O)O—(C₁-C₆ alkylene)-phenyl;    -   i. —NR^(a)R^(b), wherein R^(a) and R^(b) are independently        selected from the group consisting of H and C₁-C₆ alkyl        optionally substituted by OH, halo, CN, —C(O)OH, phenyl, and 3-7        membered heterocycloalkyl;

R^(2a) is selected from the group consisting of H, C₁-C₆ alkyloptionally substituted by OH, and phenyl;

R^(3a) is selected from the group consisting of H, C₁-C₆ alkyloptionally substituted by OH, and phenyl;

Ring A is a 3-7 membered heterocycloalkyl; and

Ring B is a 3-7 membered heterocycloalkyl or a 3-7 memberedheterocyclyalkenyl, wherein p¹ a is 0, 1 or 2 and p^(2a) is 0, 1 or 2,

provided that Ring A and Ring B together form a 6-11 membered bicyclicheterocycloalkyl.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (III):

wherein:

R^(0c) is H or NH₂;

R³ is (i) or (ii):

wherein:

-   -   R^(1c) is selected from the group consisting of H, C₁-C₆ alkyl,        —(C₁-C₆ alkyl)-phenyl, —C(O)—(C₁-C₆ alkyl), —C(O)-phenyl, and        4-6 membered heterocycloalkyl;    -   R^(2c) is H or C₁-C₆ alkyl; and    -   R^(3c) is a bond or C₁-C₆ alkylene optionally substituted by        oxo; or    -   R^(1c) and R^(2c) together form a 3-11 membered heterocycloalkyl        optionally substituted by C₁-C₆ alkyl, oxo, or —(C₁-C₆        alkylene)-phenyl; or    -   R^(1c) and R^(3c) together form a 3-7 membered heterocycloalkyl;

(ii) H; C₁-C₆ alkyl optionally substituted by OH, —SO₂—(C₁-C₆ alkyl),phenyl, or —O—(C₁-C₆ alkylene)-phenyl; —(C₁-C₆ alkylene)-C(O)O(C₁-C₆alkyl); or 4-6 membered heterocycloalkyl optionally substituted by—C(O)(C₁-C₆ alkyl); and

Ring G is a 3-7 membered heterocycloalkyl wherein p^(1C) is 0, 1 or 2and p²C is 0, 1 or 2.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (IV):

wherein:

R^(0d) is H or NH₂;

R^(1d) is 3-11 membered heterocycloalkyl or —C(O)-3-11 memberedheterocycloalkyl, wherein the heterocycloalkyl is optionally substitutedC₁-C₆ alkyl, CF₃, or fluoro, or R^(1d) is —(C₁-C₆ alkylene)-NR^(v)R^(w),wherein R^(v) and R^(w) are independently H or C₁-C₆ alkyl optionallysubstituted by halo.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (V):

wherein:

R^(0e) is H or NH₂;

R^(1e) is selected from the group consisting of

-   -   a. H,    -   b. C₁-C₆ alkyl optionally substituted by halo, CN, or phenyl,    -   c. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        cycloalkyl is optionally substituted by CN,    -   d. —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein the        heterocycloalkyl is optionally substituted by C₁-C₆ alkyl;

R^(2e) is H or C₁-C₆ alkyl;

or R^(1e) and R^(2e) together form a 3-11 membered heterocycloalkyloptionally substituted by halo or —NR^(v)R^(w), wherein R^(v) and R^(w)are independently H or C₁-C₆ alkyl optionally substituted by halo;

R^(3e) is a bond or C₁-C₆ alkylene optionally substituted by oxo; and

Ring H is a 3-7 membered heterocycloalkyl wherein p^(1e) is 0, 1 or 2and p^(2e) is 0, 1 or 2.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (VI):

wherein:

R^(0f) is H or NH₂;

R^(1f) is selected from the group consisting of C₁-C₆ alkyl optionallysubstituted by halo, —C(O)OH, oxetan-3-ylmethyl, 3-6 memberedcycloalkyl, 3-11 membered heterocycloalkyl, —S—(C₁-C₆ alkyl), 5-10membered heteroaryl or phenyl, or 3-11 membered heterocycloalkenyloptionally substituted by oxo; and

Ring J is a 6-7 membered heterocycloalkyl wherein p^(1f) is 1 or 2 andp^(2f) is 1 or 2.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (VII):

wherein:

R^(0g) is H or NH₂;

R^(1g) is selected from the group consisting of C₁-C₆ alkyl;

R^(2g) is selected from the group consisting of C₁-C₆ alkyl.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (VIII):

wherein:

R^(0h) is H or NH₂;

R^(1h) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by CN, 3-6 membered cycloalkyl, or 4-6 memberedheterocycloalkylene-C(O)O—(C₁-C₆ alkylene)-phenyl;

Ring C is 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and

Ring D is a 3-7 membered heterocycloalkyl substituted at the solenitrogen by R^(1h); and

provided Rings C and D together form a 3-11 membered spiroheterocycloalkyl.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (IX):

wherein:

R^(0j) is H or NH₂;

R^(3j) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by OH, 3-6 membered cycloalkyl, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ alkyl)-OH, —SO₂—(C₁-C₆ alkyl) and phenyl, wherein the phenylis optionally substituted by CN;

R^(4j) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by OH;

or R^(3j) and R^(4j) together form a 4-6-membered heterocycloalkyl;

R^(5j) is selected from the group consisting of H and C₁-C₆ alkyl; and

Ring K is a 6-7 membered heterocycloalkyl wherein p^(1j) is 1 or 2 andp^(2j) is 1 or 2.

In some embodiments, a compound of Formula (00A), (0A) or (A) is furtherdefined as a compound of Formula (X):

wherein:

R^(0k) is H or NH₂;

R^(1k) is selected from the group consisting of

-   -   a. H,    -   b. C₁-C₆ alkyl optionally substituted by halo, CN, or phenyl,    -   c. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the        cycloalkyl is optionally substituted by CN,    -   d. —(C₁-C₆ alkylene)-4-6 membered heterocycloalkyl wherein the        heterocycloalkyl is optionally substituted by C₁-C₆ alkyl;

R^(2k) is selected from the group consisting of H and C₁-C₆ alkyl;

or R^(1k) and R^(2k) together form a 3-11 membered heterocycloalkyloptionally substituted by halo; C₁-C₆ alkyl optionally substituted byOH; or —NR^(v)R^(w), wherein R⁰ and R^(w) are independently H or C₁-C₆alkyl optionally substituted by halo; and

R^(3k) is a bond, methylene, or —C(═O)—.

In some embodiments, X^(A) and X^(B) are independently selected from thegroup consisting of 3-6-membered cycloalkyl, 6-10 membered aryl, 5-6membered heterocycloalkenyl, and 5-10 membered heteroaryl, wherein eachof X^(A) and X^(B) are independently optionally substituted by Y¹.

In some embodiments, either X^(A) or X^(B) is a 3-11 memberedheterocycloalkyl optionally substituted by Y¹.

In some embodiments, Ring Q is (i). In some embodiments Ring Q is (ii).

In some embodiments, t¹ is 0. In some embodiments, t¹ is 1.

In some embodiments, R⁰, R⁰⁰ and R⁰¹ are each H.

In some embodiments, R⁰ is NH₂.

In some embodiments, Ring Q is (i), t¹ is 0 or 1, and R⁰, R⁰⁰ and R⁰¹are each H.

In some embodiments, Ring Q is (ii), t² is 0 or 1, and R⁰, R⁰⁰ and R⁰¹are each H.

In some embodiments, Ring Q is (i), t¹ is 1, and X^(A) is NR^(a)R^(b),wherein R^(a) and R^(b)are each independently H, C₁-C₆ alkyl optionallysubstituted with 5-6 membered heteroaryl, or 3-6 membered cycloalkyloptionally substituted by OH, halo, CN, or C₁-C₆ alkyl optionallysubstituted by OH.

In some embodiments, Ring Q is (i), t¹ is 0, and X^(A) is C₁-C₆ alkyl or3-6 membered cycloalkyl, wherein X^(A) is optionally substituted by—NR^(a)R^(b), wherein R^(a) and R^(b) are independently H or C₁-C₆alkyl.

In some embodiments, a compound is selected from Table 1 or of Examples1-468.

Also provided is a pharmaceutical composition comprising a5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), (0A) or (A), or asubformula thereof, and a pharmaceutically acceptable carrier, diluentor excipient.

Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), (0A) or (A), or asubformula thereof, in therapy is also provided.

Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), (0A) or (A), or asubformula thereof, in the treatment of an inflammatory disease, such asasthma, is also provided.

Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), (0A) or (A), or asubformula thereof, for the preparation of a medicament for thetreatment of an inflammatory disease, such as asthma, is also provided.

Also provided is a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidinecompound as described herein, such as a compound of Formula (00A), (0A)or (A), or a subformula thereof, for use in the treatment of aninflammatory disease, such as asthma.

Also provided is a method of preventing, treating or lessening theseverity of a disease or condition responsive to the inhibition of aJanus kinase activity in a patient, comprising administering to thepatient a therapeutically effective amount of a5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound asdescribed herein, such as a compound of Formula (00A), (0A) or (A), or asubformula thereof. In some embodiments, the disease or condition isasthma. In some embodiments, the Janus kinase is JAK1. In someembodiments, a compound is administered via inhalation.

In some embodiments, such as a compound of Formula (00A), (0A) or (A),R⁰⁰ is H or CH₃; R⁰¹ is H or NH₂; R⁰ is H or NH₂; and Ring Q is either(i) or (ii):

wherein t¹ and t² are each independently 0 or 1, and X^(A) and X^(B) areeach independently selected from the group consisting of:

In some embodiments, such as a compound of Formula (00A), (0A) or (A),R⁰⁰ is H or CH₃; R⁰¹ is H or NH₂; R⁰ is H or NH₂; and Ring Q is either(i) or (ii):

wherein t¹ and t² are each independently 0 or 1, and X^(A) and X^(B) areeach independently selected from the group consisting of:

In any embodiment herein, one or more compounds of WO 2011/003065 is/areexcluded.

Also provided is a compound selected from Examples 1-468 or Table 1, orany combination thereof. If any discrepancy exists between a structureand its chemical name, the structure prevails.

TABLE 1 Exemplary Compounds of the Present Invention Ex. Structure Name 1

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  2

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-(4-piperdyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  3

N-[1-[2-[(3aS,6aR)-2- methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  4

N-[1-[2-[(3aR,6aS)- 2,3,3a,4,6,6a-hexahydro- 1H-pyrrolo[3,4-c]pyrrol-5-yl]-2-oxoethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  5

N-[1-[2-[(3aS,6aR)-2- ethyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  6

N-[1-[2-[(3aS,6aR)-2- (cyclopropylmethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  7

N-[1-[2-[(3aS,6aR)-2- methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]-5-amino- pyrazolo[1,5- a]pyrimidine-3- carboxamide  8

N-[1-[2-[(3aR,6aS)-2- methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]-6-methyl- pyrazolo[1,5- a]pyrimidine-3- carboxamide  9

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  10

N-[1-[2-(2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl)-2-oxo-ethyl]-3-[5-chloro- 2- (difluoromethoxy)phenyl]pyrazol-4-yl]-2-amino- pyrazolo[1,5- a]pyrimidine-3- carboxamide  11

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-ethyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  12

N-[1-[2-[(3aS,6aR)-2- isopropyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  13

N-[1-[2-[(3aS,6aR)-2-(2- phenylethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  14

N-[1-[2-[(3aR,6aS)-2-(3- hydroxypropyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  15

3-hydroxypropyl (3aR,6aS)-2-[2-[3-[5- chloro-2-(difluoromethoxy)phenyl]- 4-(pyrazolo[1,5- a]pyrimidine-3-carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate  16

N-[1-[2-[(3aR,6aR)-2- methyl-3a-phenyl- 3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]- 2-oxo-ethyl]-3-[5-chloro- 2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  17

benzyl 4-[[(3aR,6aS)-5-[2- [3-[5-chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]acetyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-2-yl]methyl]piperidine-1- carboxylate  18

N-[1-[2-[(3aR,6aS)-2-[3- (2-oxopyrrolidin-1- yl)propyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  19

N-[1-[2-[(3aR,6aS)-2-(3- morpholinopropyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  20

N-[1-[2-[(3aR,7aS)- 2,3,3a,4,5,6,7,7a- octahydropyrrolo[3,2-c]pyridin-1-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  21

N-[1-[2-[(3aS,7aR)- 1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,4-c]pyridin-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  22

N-[1-[2-[(3aS,6aR)-2-[(1- acetyl-4- piperidinyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  23

ethyl 4-[[(3aS,6aR)-5-[2- [3-[5-chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]acetyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-2-yl]methyl]piperidine-1- carboxylate  24

N-[1-[2-[(3aS,7aR)-5- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  25

N-[1-[2-[(3aR,7aS)-2- methyl-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-5- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  26

N-[1-[2-[(3aR,6aS)-2- (tetrahydropyran-4- ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  27

N-[1-[2-[(3aS,6aR)-2-(3- methylsulfonylpropyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  28

N-[1-[2-[(3aS,6aR)-2- isobutyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  29

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(1-methyl-3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridin-5-yl)-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  30

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(5-methyl-3,3a,4,6,7,7a-hexahydro- 1H-pyrrolo[3,4-c]pyridin-2-yl)-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  31

N-[1-[2-[(3aS,6aR)-2-(2- methylsulfonylethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  32

N-[1-[2-[(3aS,6aR)-2-[3- (2-oxooxazolidin-3- yl)propyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  33

N-[1-[2-[(3aR,6aS)-2- [(4,4- difluorocyclohexyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  34

N-[1-[2-[(3aR,6aS)-2-[(1- methylsulfonyl-4- piperidyl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  35

N-[1-[2-[(3aR,6aS)-2-[[1- (tetrahydropyran-4- carbonyl)-4-piperdyl]methyl]- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  36

N-[1-[2-[(3aR,6aS)-2-[[1- (dimethylcarbamoyl)-4- piperidyl]methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  37

N-[1-[2-[(3aS,4S,6R,6aR)- 6-(hydroxymethyl)-2- methyl-4-phenyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  38

N-[1-[2-[(3aR,6aS)-2-(3- methoxypropyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  39

N-[1-[2-[(3aR,6aS)-2-[(3- methyloxetan-3- yl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  40

N-[1-[2-[(3aR,6aS)-2- (cyclobutylmethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  41

N-[1-[2-[(3aR,7aS)-1- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-5- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  42

N-[1-[2-[(3aS,7aR)-1- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-5- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  43

N-[1-[2-[(3aS,6aS)-2- methyl-3a-phenyl- 3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]- 2-oxo-ethyl]-3-[5-chloro- 2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  44

N-[1-[2-[(3aR,6aR)-2- methyl-3a-phenyl- 3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]- 2-oxo-ethyl]-3-[5-chloro- 2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  45

N-[1-[2-[(3aS,7aR)-5- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  46

N-[1-[2-[(3aS,6aR)-2-[(1- hydroxycyclohexyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  47

N-[1-[2-[(3aS,6aR)-2-[(1- cyanocyclohexyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  48

N-[1-[2-[(3aR,7aS)-5- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  49

N-[1-[2-[(3aS,7aS)-5- methyl-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-2- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  50

N-[1-[2-[(3aR,6aS)-2-(3- hydroxy-3-methyl-butyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  51

3-[(3aR,6aS)-5-[2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]acetyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-2-yl]propylmorpholine-4-carboxylate  52

N-[1-[2-[(3aR,6aS)-2- (cyclohexylmethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  53

N-[1-[2-[(3aR,7aR)-5- methyl-3,3a,4,6,7,7a- hexahydro-1H-pyrrolo[3,4-c]pyridin-2- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  54

N-[1-[2-[(3aR,6aS)-2-[3- (2-oxoindolin-1- yl)propyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  55

3-[(3aS,6aR)-5-[2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]acetyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-2-yl]propylcyclobutanecarboxylate  56

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(1-methyl-3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridin-5-yl)-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  57

N-[1-[2-[(3aS,6aR)-2- (cyclopropylmethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-a]pyrimidine-3- carboxamide  58

N-[1-[2-[(3aS,6aR)-2- [(4,4- difluorocyclohexyl)methyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrolo-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-a]pyrimidine-3- carboxamide  59

N-[1-[2-[(3aR,6aS)-2- (2,2,2-trifluoroethyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  60

N-[1-[2-[(3aR,6aS)-2-[2- [(4- chlorophenyl)methoxy]ethyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  61

N-[1-[2-[(3aR,7aR)-5- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  62

N-[1-[2-[(3aS,7aS)-5- methyl-3,3a,4,6,7,7a- hexahydro-2H-pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5- chloro-2-(difluoromethoxyphenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  63

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-cyanoethyl(methyl)amino]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidin-3- carboxamide  64

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[3-(dimethylamino)azetidin- 1-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  65

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[3-(dimethylamino)pyrrolidin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  66

N-[1-[2-(4-amino-1- piperidyl)-2-oxo-ethyl]-3- [5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  67

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(dimethylamino)-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  68

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-methoxyethyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrazolo[1,5- a]pyrimidine-3- carboxamide  69

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(4-pyrrolidin-1-yl-1- piperidyl)ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  70

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(dimethylamino)methyl]- 1-piperdyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  71

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R)-3-[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  72

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  73

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(dimethylamino)ethoxy]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  74

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(dimethylamino)methyl]- 4-hydroxy-1-piperidyl]-2- oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  75

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-[4-(ethylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  76

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(3R)-3-hydroxypyrrolidin-1-yl]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  77

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(3S)-3-hydroxypyrrolidin-1-yl]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  78

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2R)-2-[(dimethylamino)methyl] pyrrolidin-1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  79

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2S)-2-[(dimethylamino)methyl] pyrrolidin-1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  80

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(dimethylamino)methyl]- 4-phenyl-1-piperidyl]-2- oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  81

N-[1-[2-[(2S)-2- (aminomethyl)pyrrolidin- 1-yl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  82

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  83

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(methylamino)-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide  84

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(cyclobutylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  85

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2-phenylethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  86

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[2-(2-pyridyl)ethyl]amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  87

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-cyanoethylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  88

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[[4-(dimethylamino)-4-oxo- butyl]-methyl-amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  89

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(2-phenylethylamino)-1- piperidyl]ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  90

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-4-hydroxyphenyl)ethyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  91

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-hydroxyphenyl)ethylamino]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  92

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-chlorophenyl)ethylamino]- 1-piperidyl]-2-oxo- ethyl]pyrazolo-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  93

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-[2-[4-(trifluoromethyl)phenyl] ethylamino]-1- piperidyl]ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  94

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-chlorophenyl)ethyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  95

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-methoxyphenyl)ethyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  96

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[(3-methyloxetan-3- yl)methyl]amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  97

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[2-[4-(trifluoromethyl)phenyl] ethyl]amino]-1-piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide  98

N-[1-[2-[4- [benzyl(methyl)amino]-1- piperidyl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide  99

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2,2,2-trifluoroethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 100

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2-phenoxyethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 101

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-cyclohexylethyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 102

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(2,2-difluoro-2-phenyl-ethyl)-methyl- amino]-1-piperidyl]-2- oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 103

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-[2-phenylethyl(2,2,2- trifluoroethyl)amino]-1- piperidyl]ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 104

N-[1-[2-[4-[2-(4- bromophenoxy)ethyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 105

N-[1-[2-[4-[2-(2- bromophenoxy)ethyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 106

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(2-chlorophenoxy)ethyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 107

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-chlorophenoxy)ethyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 108

N-[1-[2-[4-[butyl-[2-(4- methylphenoxy)ethyl] amino]-1-piperidyl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 109

N-[1-[2-[4-[allyl-[2-(4- methylphenoxy)ethyl] amino]-1-piperidyl]-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 110

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[2-(4-methylphenoxy)ethyl] amino]-1-piperidyl]-2-oxo- ethyl]pyazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 111

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(4,4-difluoro-1-piperidyl)methyl]-4- phenyl-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 112

N-[1-[2-[4-[1,3- benzodioxol-2- ylmethyl(methyl)amino]-1-piperidyl]-2-oxo-ethyl]- 3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 113

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[(3-phenoxyphenyl)methyl] amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 114

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(1-cyanocyclohexyl)methyl- methyl-amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 115

N-[1-[2-[4-[butyl(2,2,2- trifluoroethyl)amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 116

N-[1-[2-[4-[benzyl(2,2,2- trifluoroethyl)amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 117

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(3-methyloxetan-3-yl)methyl-(3,3,3- trifluoropropyl)amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 118

N-[1-[2-[4-[benzyl(3,3,3- trifluoropropyl)amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 119

N-[1-[2-[4-[(4- beromophenyl)methyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 120

N-[1-[2-[4-[(4-tert- butylphenyl)methyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 121

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(3,4-dichlorophenyl)methyl- methyl-amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 122

N-[1-[2-[4-[(3- bromophenyl)mehtyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 123

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(3-phenylpropyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 124

[1-[2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)pyrazol-1- yl]acetyl]-4-piperidyl]-dimethyl-(3- phenylpropyl)ammonium 125

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(4-isopropoxyphenyl)methyl- methyl-amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 126

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(4-chlorophenyl)methyl- methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 127

N-[1-[2-[4-[(4- butoxyphenyl)methyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 128

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[[3-(trifluoromethyl)phenyl] methyl]amino]-1-piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 129

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(2,4-dimethylphenyl)methyl- methyl-amino]-1- piperidyl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 130

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2-naphthylmethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 131

N-[1-[2-[4-[(3-bromo-4- fluoro-phenyl)methyl- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 132

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-[(2,2,2-trifluoro-1-phenyl- ethyl)amino]-1- piperidyl]ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 133

N-[1-[2-[4-[(1-benzyl- 2,2,2-trifluoro-ethyl)- methyl-amino]-1-piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]p0yrimidine-3- carboxamide 134

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2,2-difluoropropyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 135

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(5-chloroisoindolin-2-yl)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 136

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[3-(dimethylamino)pyrrolidin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 137

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(dimethylamino)ethoxy]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 138

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[3-(dimethylamino)azetidin- 1-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 139

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-[4-(dimethylamino)- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 140

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-hydroxyethyl(methyl)amino]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 141

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-methoxyethyl(methyl) amino]-1-piperidiyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 142

N-[1-[1-(3- acetamidopropyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 143

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-oxo-4-(1-piperidyl)butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 144

N-[1-[1-(1-acetyl-4- piperidyl)-4-piperidyl)]-3- [5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-a]pyrimidine-3- carboxamide 145

2-amino-N-[1-[1-(3- benzamidopropyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 146

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-[3-(2-oxopyrrolidin- 1-yl)propyl]-4- piperidyl]pyrazol-4-yl]pyrazolo-4-[1,5- a]pyrimidine-3- carboxamide 147

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-(4-morpholino-4-oxo- butyl)-4-piperidyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 148

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-[4-(dimethylamino)- 4-oxo-butyl]-4- piperidyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 149

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-[4-(methylamino)-4- oxo-butyl]-4- piperidyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 150

N-[1-[1-(3- acetamidopropyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-a]pyrimidine-3- carboxamide 151

2-amino-N-[1-[1-[3- [benzoyl(methyl)amino] propyl]-4-piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 152

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-oxo-4-(tetrahydropyran-4- ylamino)butyl]-4- piperidyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 153

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-(oxetan-3-ylamino)-4-oxo-butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 154

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(3-methyl-2-oxo-imidazolidin-1-yl)propyl]- 4-piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 155

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(2-oxopyrrolidin-1-yl)propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 156

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-(ethylamino)-4-oxo-butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 157

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[2-(methylamino)-2-oxo-ethyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 158

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-(3-morpholinopropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 159

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-(3-thiomorpholinopropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 160

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(methylamino)-3-oxo-propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 161

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 162

2-amino-N-[1-[1-(4- amino-4-oxo-butyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 163

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(2-oxoimidazolidin-1- yl)propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 164

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-[3-(3-methyl-2-oxo- imidazolidin-1-yl)propyl]-4-piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 165

2-amino-N-[1-[1-(3- amino-3-oxo-propyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 166

2-amino-N-[1-[1-[3-(3- benzyl-2-oxo- imidazolidin-1-yl)propyl]-4-piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1-5 a]pyrimidine-3- carboxamide 167

2-amino-N-[1-[1-[4- (benzylamino)-4-oxo- butyl]-4-piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 168

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-(methylamino)-4-oxo-butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 169

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-(4-morpholino-4-oxo-butyl)-4-piperdyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 170

N-[1-[1-(4-amino-4-oxo- butyl)-4-piperidyl]-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 171

2-amino-N-[1-(azepan-4- yl)-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 172

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(1-methylazepan-4-yl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 173

N-[1-[1-[(1-acetyl-4- piperidyl)methyl]-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-a]pyrimidine-3- carboxamide 174

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(1-isobutyl-4-piperidyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 175

ethyl 4-[4-[4-[(2- aminopyrazolo[1,5- a]pyrimidine-3-carbonyl)amino]-3-[5- chloro-2- (difluoromethoxy)phenyl]pyrazol-1-yl]-1- piperidyl]butanoate 176

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-(3-hydroxypropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 177

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-(3-methylsulfonylpropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 178

2-amino-N-[1-(1-benzyl- 4-piperidyl)-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 179

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[1-(4-phenylbutyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 180

2-amino-N-[1-[1-(2- benzyloxyethyl)-4- piperidyl]-3-[5-chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 181

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-(2-phenylethoxy)butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 182

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(3S)-1-methylpyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 183

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(3R)-1-methylpyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 184

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(1-methyl-4-piperidyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 185

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[(3R)-pyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 186

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[(3S)-pyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidin-3-carboxamide 187

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[4-[4-[(1-cyanocyclohexyl)methyl- methyl-amino]piperidine- 1-carbonyl]phenyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide188

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(dimethylamino)-1-piperidyl]thiazolo-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 189

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[2-cyanoethyl(methyl)amino]- 1-piperidyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 190

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(dimethylamino)methyl]- 1-piperidyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 191

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[2-(dimethylamino)ethyl]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 192

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[methyl(2-phenylethyl)amino]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 193

N-[2-[4-[(4-amino-4-oxo- butyl)-methyl-amino]-1-piperidyl]-4-[5-chloro-2- (difluoromethoxy)phenyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 194

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(3-fluoroazetidin-1-yl)-1-piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide195

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[3-(1-piperidyl)azetidin-1-yl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 196

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]thiazol- 5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 197

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[4-(dimethylamino)piperidine- 1-carbonyl]-1- piperidyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 198

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[methyl(2,2,2-trifluoroethyl)amino]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 199

N-[2-[4- [butyl(methyl)amino]-1- piperidyl]-4-[5-chloro-2-(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 200

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[methyl-[(3-methyloxetan-3- yl)methyl]amino]-1- piperidyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 201

N-[2-[4- [benzyl(methyl)amino]-1- piperidyl]-4-[5-chloro-2-(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 202

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[4-[methyl(2,2,2-trifluoroethyl)amino]piperidine- 1-carbonyl]-1- piperidyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 203

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(1-cyanocyclohexyl)methyl- methyl-amino]-1- piperidyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 204

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[4-[(1-cyanocyclohexyl)methyl- methyl-amino]piperidine- 1-carbonyl]-1-piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 205

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-(4-methylpiperazin-1-yl)thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 206

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(2-phenylethyl)piperiazin-1- yl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 207

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4- (cyclopropylmethyl)piperazin-1-yl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide208

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 209

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[3- (dimethylamino)prop-1-ynyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 210

N-[2-[3- [butyl(methyl)amino]prop- 1-ynyl]-4-[5-chloro-2-(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 211

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-diazaspiro[3.4]octan-2-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 212

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-diazaspiro[4.4]nonan-2- yl)-2-oxo-ethyl]pyrazolo-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 213

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 214

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(6-methyl-2,6-diazaspiro[3.3]heptan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 215

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(9-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-4-yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide216

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-diazaspiro[3.5]nonan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 217

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,7-diazaspiro[3.5]nonan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 218

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,7-diazaspiro[3.5]nonan-7- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 219

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,6-diazaspiro[3.4]octan-6-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 220

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,7-diazaspiro[3.4]octan-2-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 221

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 222

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(8-methyl-2,8-diazaspiro[4.5]decan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 223

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,8-diazaspiro[4.5]decan-8- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 224

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,8-diazaspiro[4.5]decan-8- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 225

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-isobutyl-2,8-diazaspiro[4.5]decan-8- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 226

benzyl 4-[[8-[2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]acetyl]-2,8- diazaspiro[4.5]decan-2- yl]methyl]piperidine-1-carboxylate 227

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide228

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-hydroxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 229

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-methoxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 230

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(3-hydroxypropyl)piperazin- 1-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 231

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(2-hydroxyethoxy)ethyl]piperazin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 232

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-methylsulfonylethyl)piperazin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 233

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-ethylpiperazin-1-yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide234

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R)-3-(hydroxymethyl)-4- methyl-piperazin-1-yl]-2- oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 235

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-(hydroxymethyl)-4- methyl-piperazin-1-yl]-2- oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 236

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(4-phenylpiperazin-1- yl)ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 237

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(4-cyanophenyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 238

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(4-cyanophenyl)methyl]piperazin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 239

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 240

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 241

N-[1-[2-(1,3,4,6,7,8,9,9a- octahydropyrido[1,2- a]pyrazin-2-yl)-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 242

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(1S,5R)-8-methyl- 3,8-diazabicyclo[3.2.1]octan- 3-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 243

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(4-methylpieprazin-1- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 244

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-hydroxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 245

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-methoxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 246

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 247

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(4-ethylpiperazin-1- yl)-2-oxo-ethyl]pyazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 248

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(cyclopropylmethyl)piperazin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 249

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-(2-oxo-2-piperazin-1-yl- ethyl)pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 250

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-[(1S,4S)-5-methyl- 2,5- diazabicyclo[2.2.1]heptan-2-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 251

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 252

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-[(1R,4R)-5-methyl- 2,5- diazabicyclo[2.2.1]heptan-2-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 253

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[4-(dimethylamino)piperidine- 1- carbonyl]phenyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 254

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-(4-pyridyl)thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 255

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(dimethylamino)methyl] phenyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 256

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(3-fluoroazetidin-1-yl)methyl]phenyl]thiazol- 5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide257

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(3,3-difluoroazetidin-1- yl)methyl]phenyl]thiazol- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 258

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(4-methylpiperazin-1-yl)phenyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 259

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(4-methylpiperazine-1-carbonyl)phenyl]thiazol- 5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 260

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[[4-(dimethylamino)-1-piperidyl]methyl]thiazol- 5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide261

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[[methyl(2-phenylethyl)amino]methyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 262

N-[2-[[(3aR,6aS)-2- methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl]methyl]-4- [5-chloro-2- (difluoromethoxy)phenyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 263

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-(1-piperidylmethyl)thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide264

N-[2-[(3aR,6aS)-2-methyl- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-4- [5-chloro-2- (difluoromethoxy)phenyl]thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 265

N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(dimethylamino)piperidine- 1-carbonyl]thiazol-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 266

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-[4-(hydroxymethyl)- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 267

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2S)-2-(1,2-dihydroxyethyl)pyrrolidin- 1-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 268

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2S)-2-(hydroxymethyl)pyrrolidin- 1-yl]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 269

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 270

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-hydroxypyrrolidin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 271

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R)-3-hydroxypyrrolidin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 272

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-hydroxy-4-(hydroxymethyl)-1- piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 273

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[2-(hydroxymethyl)morpholin- 4-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 274

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(hydroxymethyl)-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 275

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-hydroxyethoxy)-1- piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 276

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-hydroxy-4-(4-pyridyl)-1-piperidyl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 277

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[2-(hydroxymethyl)morpholin- 4-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 278

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-hydroxy-1-piperidyl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 279

2-amino-N-[1-[2-(4- benzyl-4-hydroxy-1- piperidyl)-2-oxo-ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 280

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-hydroxy-4-methyl-1-piperidyl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 281

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-cyano-4-phenyl-1-piperidyl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 282

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,3-difluoropyrrolidin-1-yl)-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 283

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(4-cyano-4-phenyl-1- piperidyl)-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 284

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,6-dihydro-2H-pyridin-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 285

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-oxo-2-(4-phenoxy-1- piperidyl)ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 286

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(4-hydroxy-4-phenyl- 1-piperidyl)-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 287

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,3-difluoropyrrolidin-1-yl)-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 288

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-morpholino-2-oxo-ethyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 289

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-hydroxy-4-phenyl-1-piperidyl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 290

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-(2-morpholino-2-oxo- ethyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 291

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[[1-(hydroxymethyl)cyclopropyl] methylamino]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 292

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(1-hydroxycyclopentyl)methyl] pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 293

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[[1-(hydroxymethyl)cyclopropyl]- methyl-amino]-2-oxo- ethyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 294

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methoxyethylamino)ethyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 295

2-amino-N-[1-(2- aminoethyl)-3-[5-chloro- 2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 296

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(1S,3R)-3-(methylamino)cyclohexyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 297

2-amino-N-[1-(3- aminocyclobutyl)-3-[5- chloro-2-(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 298

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[3-(methylamino)cyclobutyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 299

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[ethyl-[(2-methyl-4-pyridyl)methyl]amino]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 300

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2-chloro-4-pyridyl)methyl-ethyl- amino]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 301

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[ethyl(3-pyridylmethyl)amino]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 302

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[4-[4-(dimethylamino)piperidine- 1- carbonyl]phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-4- carboxamide 303

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[4-[4-[methyl(2,2,2-trifluoroethyl)amino] piperidine-1- carbonyl]phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 304

N-[1-(3-amino-3-imino- propyl)-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 305

N-[1-(4-amino-4-imino- butyl)-3-[5-chloro-2- (difluoromethoxy)phenyl]pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 306

ethyl 2-[2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-a]pyrimidine-3- carbonylamino)pyrazol-1- yl]ethylamino]acetate 307

cyclopentyl 2-[2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-yl]ethylamino]acetate 308

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(1-piperidyl)ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide309

ethyl (2S)-2-amino-4-[3- [5-chloro-2- (difluoromethoxy)phenyl]-4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1- yl]butanoate310

2-[4-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperazin-1- yl]aceticacid 311

2-[[1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]ethyl)piperidin-4-yl]amino]acetic acid 312

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[2-(methylsulfanyl)ethyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 313

N-[1-[2- (benzylamino)ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 314

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(pyridin-2-ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 315

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(pyridin-4-ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 316

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(1-phenylethyl)piperazin-1- yl]ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 317

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-methylpropyl)piperazin-1- yl]-2-oxoethyl]-1H- pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 318

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1- yl]-2-oxoethyl)-1H- pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 319

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(4-propylpiperazin-1- yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 320

N-[1-[2-(4- benzylpiperazin-1-yl)-2- oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 321

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[2-(morpholin-4-yl)ethyl] piperazin-1-yl]- 2-oxoethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 322

methyl 2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]acetate 323

N-[3-[5-chloro-2- (difluoromethoxy)pyridin- 3-yl]-1-[(5-oxooxolan-2-yl)methyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidie-3- carboxamide 324

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 325

N-[3-[5-chloro-2- (difluoromethoxy7)phenyl]- 1-(2-[4-[(dimethylcarbamoyl)methyl] piperazin-1-yl]-2- oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 326

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(2-hydroxyphenyl)methyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 327

N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-(2-[[(3-hydroxyphenyl)methyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 328

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(4-hydroxyphenyl)methyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 329

methyl 2-[[1-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a] pyrimidine-3-amido]-1H- pyrazol-1-yl]acetyl)piperidin-4- yl]amino]acetate 330

N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1- yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 331

methyl 3-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]propanoate 332

3-[4-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H- pyrazol-1- yl]acetyl)piperazin-1- yl]propanoate333

methyl1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]ethyl]piperidine-4- carboxylate 334

ethyl 1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a] pyrimidine-3-amido]-1H- pyrazol-1-yl]acetyl)piperazin-1- yl]ethyl]piperidine-4- carboxylate 335

methyl 1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]ethyl]-4- methylpiperidine-4- carboxylate 336

2-(morpholin-4-yl)ethyl 1- (2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperidine-4- carboxylate 337

ethyl 1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]ethyl]-4- methylpiperidine-4- carboxylate 338

2-(dimethylamino)ethyl 1- (2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperidine-4- carboxylate 339

2-(morpholin-4-yl)ethyl 1- (2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo [1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4- carboxylate 340

2-(dimethylamino)ethyl 1- (2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4- methylpiperidine-4- carboxylate 341

piperidin-4-ylmethyl 1-(2- [3-[5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperidine-4- carboxylate 342

1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylicacid 343

1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-4-yl]acetyl)-4- methylpiperidine-4-carboxylic acid 344

N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2- yl)methyl]amino]piperidin- 1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 345

methyl 3-[[1-(2-[3-[5- choloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperidin-4-yl](methyl)amino]propanoate 346

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-([[4-(methylsulfanyl)phenyl] methyl]amino)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 347

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(2-oxooxan-4-yl)piperazin-1-yl]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 348

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]- 2-oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 349

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(4-methylpiperazin-1- yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 350

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[(4-methylpiperazin-1- yl)methyl]piperidin-1-yl]- 2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 351

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-oxo-2-[4-[(5-oxo-2,5-dihydrofuran-3- yl)methyl]piperazin-1- yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 352

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3- yl)methyl]amino]piperidin- 1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 353

3-[4-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperazin-1- yl]propanoicacid 354

tert-butyl (3R,4R)-4-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-3-hydroxypiperidine-1- carboxylate 355

(3S,4S)-4-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-3- hydroxypiperidine-1-carboxylate 356

(3R,4R)-3-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-4- hydroxypiperidine-1-carboxylate 357

tert-butyl (3S,4S)-3-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-4-hydroxypiperidine-1- carboxylate 358

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1- [(3R,4R)-3-hydroxypiperidin-4-yl]- 1H-pyrazol-4- yl]-pyrazolo[1,5- a]pyrimidine-3-carboxamide 359

N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-[(3S, 4S)-3-hydroxypiperidin-4-yl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 360

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(3R,4R)-4-hydroxypiperidin-3-yl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 361

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(3S, 4S)-4-hydroxypiperidin-3-yl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 362

ethyl 2-[(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]ethyl)(pyridin-3-ylmethyl)amino]acetate 363

2-[(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]ethyl)(pyridin-3-ylmethyl)amino]acetic 364

ethyl 2-[[1-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperidin-4- yl]amino]acetate 365

2-[[1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperidin-4-yl]amino]acetic acid 366

ethyl 2-(4-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]piperidin- 1-yl)acetate 367

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(1,3-oxazol-2-ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 368

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(pyridin-3-ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 369

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2S)-2-(methylamino)propyl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 370

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2S)-2-(dimethylamino)propyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 371

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2S)-2-(ethylamino)propyl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 372

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[2-(methylsulfanyl)ethyl] piperazin-1-yl]-2-oxoethyl)- 1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimdine-3- carboxamide 373

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(propan-2-yl)piperazin-1-yl]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 374

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4- (cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl]-1H- pyrazol-4-yl]pyrazolo[1,5-a]pyrimdine-3- carboxamide 375

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,4-dimethylpiperazin-1-yl)-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 376

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,4-dimethylpiperazin-1-yl)-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 377

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(2,2,4-trimethylpiperazin-1- yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 378

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-(3,3,4-trimethylpiperazin-1- yl)ethylo]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 379

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[2-(dimethylamino)ethyl] piperazin-1-yl]-2-oxoethyl)- 1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 380

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(1,3-oxazol-2-ylmethyl)piperazin-1-yl]- 2-oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 381

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 382

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-oxo-2-[4-[(5-oxooxolan-2- yl)methyl]piperazin-1- yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 383

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[(methylcarbamoyl)methyl] piperazin-1-yl]-2- oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 384

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(1R)-1-phenylethyl]amino]ethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 385

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(1S)-1-phenylethyl]amino]ethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 386

methyl 2-[(2-[3-[5-chloro- 2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]ethyl)amino]acetate 387

methyl (2S)-2-amino-4-[3- [5-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]butanoate 388

(1-methylpiperidin-4- yl)methyl 1-(2-[3-[5- chloro-2-(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylate 389

(1-methylpiperidin-4- yl)methyl 1-(2-[3-[5- chloro-2-(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4- methylpiperidine-4- carboxylate 390

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[methyl[(5-oxooxolan-2- yl)methyl]amino]ethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 391

ethyl 3-[[1-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperidin-4- yl](methyl)amino]propanoate 392

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(5-oxooxolan-3-yl)piperazin- 1-yl]ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 393

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 394

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide 395

N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2E)-4-(4-methylpiperazin-1-yl)but- 2-en-1-yl]-1H-pyrazol-4- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 396

2-(methylthio)ethyl 2-(2- (3-(5-chloro-2- (difluoroethoxy)phenyl)-4-(pyrazolo[1,5- a]opyrimidine-3- carboxamido)-1H-pyrazol-1-yl)ethylamino)acetate 397

ethyl 2-[4-(2-[3-[5-chloro- 2- (difluoromethoxy)phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]acetyl)piperazin-1- yl]acetate 398

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(4-methylpiperazine-1- carbonyl)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 399

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-((S)-tetrahydrofuran-3-ylamino)ethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 400

N-(3-(5-chloro-2- (difluoromethyl)phenyl)- 1-(2-(4-((2-oxoethyl)(methyl)amino) piperidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 401

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-(dimethylamino)-2- oxoethylamino)piperidin-1 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 402

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-((R)-tetrahydrofuran-3-ylamino)ethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamicde 403

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-hydroxy-3-morpholinopropyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 404

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(3-(dimethylamino)-2-hydroxypropyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 405

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-hydroxy-3-(piperidin-1-yl)propyl)-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide406

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-cyanoethyl)piperazin-1- yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 407

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(3-oxopiperazin-1- yl)piperidin-1-yl)ethyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 408

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(piperazine-1-carbonyl)piperidin-1- yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 409

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(3-cyanopyrrolidin-1- yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 410

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-methyl-4-morpholinopiperidin-1- yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 411

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(3-(dimethylamino)-2-oxopropyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide412

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(3-morpholino-2-oxopropyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide413

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((2-cyanopropyl)(methyl) amino)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 414

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-((S)-3-cyano-1,4′-bipiperidin-1′-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 415

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(1-methylpiperidin-4-ylidene)ethyl)-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 416

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(4-methyl-3-oxopiperazin-1- yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 417

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(2-oxopiperazin-1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 418

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-3-(piperidin-1-yl)propyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide419

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-cyanopropylamino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 420

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((2-cyanoethyl)(methyl)amino) cyclohexylidene)ethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 421

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2- cyanoethylamino)cyclohexylidene)ethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidin-3-carboxamide 422

N-(1-(2-(4- aminocyclohexylidene) ethyl)-3-(5-chloro-2-(difluoromethoxy)phenyl)- 1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 423

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(((S)-2-(dimethylcarbamoyl) pyrrolidin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide424

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((S)-2-(dimethylcarbamoyl) pyrrolidin-1-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-2- carboxamide425

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(((S)-2-(methylcarbamoyl)pyrrolidin- 1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide 426

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((S)-2-(methylcarbamoyl)pyrrolidin- 1-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 427

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((4-(2-(dimethylamino)-2- oxoethyl)piperazin-1- yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide428

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((1-(2-(dimethylamino)-2- oxoethyl)piperidin-4- yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide429

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin- 1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 430

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(1-methyl-hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 431

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((1-cyanocyclopropyl)(methyl) amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 432

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl((R)-tetrahydrofuran-3- yl)amino)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 433

N-(1-(2-(4-(((1,3- dioxolan-2- yl)amino)(methyl)amino)piperidin-1-yl)-2- oxoethyl)-3-(5-chloro-2- (difluoromethoxy)phenyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 434

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-thiomorpholinopiperidin- 1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 435

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(((1-(cyanomethyl)cyclopropyl) methyl)(methyl)amino)piperidin-1-yl)-2-oxoethyl)- 1-H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 436

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(1-cyanocyclopropylamino) piperidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 437

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(tetrahydrofuran-3- yl)piperazin-1-yl)ethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 438

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl((2-methyl-1,3-dioxolan-2- yl)methyl)amino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 439

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2- (octahydropyrrolo[3,4-b]pyridin-6-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 440

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(1-methyl-octahydropyrrolo[3,4- b]pyridin-6-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 441

N-(1-(2-(4-(1,4-oxazepan- 4-yl)piperidin-1-yl)-2-oxoethyl)-3-(5-chloro-2- (difluoromethoxy)phenyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 442

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl((S)-tetrahydrofuran-3- yl)amino)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 443

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-thiomorpholinopiperidin- 1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboaxmide oxide 444

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-((3aS,6aS)-hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 445

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(2-oxopiperazin-1- yl)piperidin-1-yl)ethyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 446

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(3-cyanoazetidin-1-yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 447

N-(1-(2-(4-((1S,4S)-5-oxa- 2-aza- bicyclo[2.2.1]heptan-2-yl)piperidin-1-yl)-2- oxoethyl)-3-(5-chloro-2- (difluoromethoxy)phenyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 448

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(4-methyl-2-oxopiperazin-1- yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carbo0xamide 449

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((R)-3-methylmiorpholino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 450

N-(1-(2-(4-(6-oxa-3-aza- bicyclo[3.1.1]heptan-3- yl)piperidin-1-yl)-2-oxoethyl)-3-(5-chloro-2- (difluoromethoxy)phenyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 451

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((S)-3-methylmorpholino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 452

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 453

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-morpholino-2-oxoethoxy)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4- yl)pyrazol[1,5-a]pyrimidine-3- carboxamide 454

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide455

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-((1-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)methyl)- 1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 456

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(3-cyanopropylamino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 457

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-((1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)- 1H-1,2,3-triazol-4- yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 458

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-((tetrahydro-2H-pyran-4- yl)methyl)piperazin-1- yl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 459

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl(oxetan-3-yl)amino)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 460

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(2-thiomorpholinoethyl) piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 461

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(3-cyanopropyl)piperazin-1- yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 462

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-cyano-1,4′-bipiperidin-1′-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 463

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2,2-difluoropropylamino) piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 464

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((3-cyanopropyl)(methyl)amino) piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 465

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((2-cyano-2-methylpropyl)(methyl)amino) piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 466

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-cyano-2-methylpropylamino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 467

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(((1-cyanocyclopropyl)methyl) (methyl)amino)piperidin- 1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 468

N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(((1-cyanocyclopropyl)methyl) amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Mixtures of particular diastereomeric compounds may beseparated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated, or enantiomerically enriched, using the sametechniques or others known in the art. Each of the asymmetric carbon ornitrogen atoms may be in the R or S configuration and both of theseconfigurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds of the presentinvention, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, including known amino-protecting andcarboxy-protecting groups which are released, for example hydrolyzed, toyield the compound of the present invention under physiologicconditions.

The term “prodrug” refers to a precursor or derivative form of apharmaceutically active substance that is less efficacious to thepatient compared to the parent drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). Prodrugs include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs oroptionally substituted phenylacetamide-containing prodrugs, and5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, forexample alkyl, alkylene or aryl, or a group having the Formula—C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same or different andare hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In aparticular embodiment, the nitrogen atom is one of the nitrogen atoms ofthe amidino group of the compounds of Formula (00A), (0A) or (A) or asubformula thereof. Prodrugs may be prepared by reacting a compound ofthe present invention, such as a compound of Formula (00A), (OA), (A),(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X),or a compound of Table 1 or of Examples 1-468, with an activated group,such as acyl groups, to bond, for example, a nitrogen atom in thecompound to the exemplary carbonyl of the activated acyl group. Examplesof activated carbonyl compounds are those containing a leaving groupbonded to the carbonyl group, and include, for example, acyl halides,acyl amines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides suchas p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, anddifluorophenoxy acyl. The reactions are generally carried out in inertsolvents at reduced temperatures such as −78 to about 50° C. Thereactions may also be carried out in the presence of an inorganic base,for example potassium carbonate or sodium bicarbonate, or an organicbase such as an amine, including pyridine, trimethylamine,triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention, such as a compound ofFormula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or suitable free carboxyl-containingcompound of Table 1 or of Examples 1-468, can be derivatized as an amideor alkyl ester. As another example, compounds of the present inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁. C₆)alkanoyl, alpha-amino(C₁-C₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

Synthesis of Janus Kinase Inhibitor Compounds

Compounds of the present invention may be synthesized by syntheticroutes described herein. In certain embodiments, processes well-known inthe chemical arts can be used, in addition to, or in light of, thedescription contained herein. The starting materials are generallyavailable from commercial sources such as Aldrich Chemicals (Milwaukee,Wis.) or are readily prepared using methods well known to those skilledin the art (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,N.Y. (1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4,Aufl. ed. Springer-Verlag, Berlin, including supplements (also availablevia the Beilstein online database)), or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds may be prepared singly or as compound libraries comprising atleast 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.Libraries of compounds may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel syntheses using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art. Thus according to a further aspect of the invention there isprovided a compound library comprising at least 2 compounds of thepresent invention, such as a compound of Formula (00A), (0A), (A), (Ia),(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or acompound of Table 1 or of Examples 1-468.

For illustrative purposes, reaction Schemes 1-26 depicted below provideroutes for synthesizing the compounds of the present invention as wellas key intermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used. Although somespecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can besubstituted to provide a variety of derivatives or reaction conditions.In addition, many of the compounds prepared by the methods describedbelow can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Other conversions commonly used in the synthesis of compounds of thepresent invention, and which can be carried out using a variety ofreagents and conditions, include the following:

-   (1) Reaction of a carboxylic acid with an amine to form an amide.    Such a transformation can be achieved using various reagents known    to those skilled in the art but a comprehensive review can be found    in Tetrahedron, 2005, 61, 10827-10852.-   (2) Reaction of a primary or secondary amine with an aryl halide or    pseudo halide, e.g., a triflate, commonly known as a    “Buchwald-Hartwig cross-coupling,” can be achieved using a variety    of catalysts, ligands and bases. A review of these methods is    provided in Comprehensive Organic Name Reactions and Reagents, 2010,    575-581.-   (3) A palladium cross-coupling reaction between an aryl halide and a    vinyl boronic acid or boronate ester. This transformation is a type    of “Suzuki-Miyaura cross-coupling,” a class of reaction that has    been thoroughly reviewed in Chemical Reviews, 1995, 95(7),    2457-2483.-   (4) The hydrolysis of an ester to give the corresponding carboxylic    acid is well known to those skilled in the art and conditions    include: for methyl and ethyl esters, the use of a strong aqueous    base such as lithium, sodium or potassium hydroxide or a strong    aqueous mineral acid such as HCl; for a tert-butyl ester, hydrolysis    would be carried out using acid, for example, HCl in dioxane or    trifluoroacetic acid (TFA) in dichloromethane (DCM).

Other exemplary transformations are discussed following the Schemesbelow.

Compounds of formula 6 can be synthesized as shown in reaction Scheme 1.Trichloroacetonitrile can be reacted with cyanoacetic acid ethyl esterto give compound 34. Compound 1 can be condensed with hydrazine to givecompound 2, which can then be condensed with 1,1,3,3-tetramethoxypropaneto give compound 3. Amine 3 can be doubly Boc-protected to give compound4, which can then be hydrolyzed with lithium hydroxide to givecarboxylic acid 5. Carboxylic acid 5 can then be coupled to variousamines in the presence of PyAOP, DIEA, and DMAP to give compounds offormula 6.

A method for the synthesis of compounds of Formula 5 is illustrated inReaction Scheme 2. α-Bromoketones can be generated from compound 1 witha reagent such as bromine. Alkylation of di-tert-butyl iminodicarbonatewith sodium hydride and various α-bromoketones 2 generates compound 3.Compound 3 can be heated with DMFDMA to give compound 4. Cyclization ofcompound 4 with hydrazine in ethanol provides pyrazole compound 5.Coupling of compound 5 with pyrazolo[1,5-a]pyrimidine-3-carboxylic acidin the presence of PyAOP, DIEA, and DMAP provides compounds of Formula6.

An alternative method for the synthesis of compounds of Formula 6 isdescribed in Reaction Scheme 3. Alkylation of potassium phthalimide withα-bromoketones 1 generates compound 2. Condensation with DMFDMA yieldscompounds 3. Compound 3 may be cyclized with hydrazine to yield compound4, which may then be coupled with pyrazolo[1,5-a]pyrimidine-3-carboxylicacid under amide formation conditions using HATU to provide compounds ofFormula 5. Alkylation of compound 5 with alkyl halides in the presenceof cesium carbonate gives compounds of Formula 6.

Reaction Scheme 4 illustrates an alternate synthesis for compounds offormula 5. Nitro-SEM pyrazole compound 1, prepared as in Reaction Scheme5, may be regioselectively deprotonated with lithiumhexamethyldisilazide at low temperature and quenched with iodine toyield 2. The nitro group of compound 2 can be reduced in the presence ofiron and ammonium chloride, followed by Boc protection to generatecompound 3. Compound 3 may be coupled under Suzuki conditions with arylboronic acids or aryl boronates to yield compounds 4. After cleavage ofthe Boc group with tin tetrachloride, compounds of formula 5 areobtained.

An alternate method for the synthesis of compounds of Formula 6a and 6bis shown in Reaction Scheme 5. Commercially available4-nitro-1H-pyrazole may be protected with a[P-(trimethylsilyl)ethoxy]methyl (SEM) group by treatment with sodiumhydride and (2-(chloromethoxy)ethyl)trimethylsilane. The resultingcompound 1 can be arylated with aryl bromides or iodides under palladiumcatalyzed conditions to generated 4-nitro-5-aryl-pyrazoles of formula 2.The nitro group of compounds 2 can be reduced in the presence of ironand ammonium chloride to generate amino pyrazoles 3. Amide bond couplingwith commercially available pyrazolo[1,5-a]pyrimidine-3-carboxylic acidin the presence of PyAOP, DIEA, and DMAP provides compounds 4. Removalof the SEM protecting group by aqueous HCl in ethanol generatescompounds 5, which may be alkylated with alkyl halides in the presenceof a suitable base such as cesium carbonate or with Michael acceptors toprovide compounds of Formula 6a and 6b.

An alternate method for the synthesis of compounds of Formula 4a and 4bis shown in Reaction Scheme 6. Commercially available4-Nitro-1H-pyrazole can be reacted with alkyl bromides in the presenceof cesium carbonate at 55° C. for 12 hours to give compound 1. Compound1 can be reacted with aryl bromides in N,N-Dimethylacetamide in thepresence of Palladium (II) acetate, Di(1-adamntyl)-n-butylphosphine,potassium carbonate and trimethylacetic acid to give compounds 2a and2b. The ratio of products 2a:2b varies depending on the substituent R1,but the reaction generally favors formation of product 2b. Compounds 32aand 32b can be reduced to compounds 3a and 3b in the presence of ironand ammonium chloride in ethanol and water. Coupling of compounds 3a and3b with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence ofPyAOP, DIEA, and DMAP can provide compounds of Formula 4a and 4b.

Amide bond coupling of 1 with5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (preparedaccording to the procedure in Journal of Medicinal Chemistry, 55(22),10090-10107; 2012) in the presence of triethylamine provides compoundsof formula 2. Treatment of 2 with aqueous ammonia generates compounds offormula 3. Removal of the SEM protecting group by aqueous HCl inmethanol generates compounds of formula 4, which may be alkylated withalkyl halides in the presence of a suitable base such as cesiumcarbonate or with Michael acceptors to provide compounds of Formula 5aand 5b.

A method for the synthesis of compounds of Formula 4a and 4b is shown inReaction Scheme 8. An amide bond coupling of compound 1 withcommercially available 6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid in the presence of HATU and DIPEA provides compound 2. Removal ofthe SEM protecting group by aqueous HCl in ethanol generates compounds3, which may be alkylated with alkyl halides in the presence of asuitable base such as cesium carbonate or with Michael acceptors toprovide compounds of Formula 4a and 4b.

Compounds of formula 4 can be synthesized as shown in reaction Scheme 9.Pyrazole compound 1 (prepared as described herein) may be alkylated witht-butyl-bromoacetate in the presence of cesium carbonate to giveintermediate 2. 2 may be treated with trifluoroacetic acid to give acids3, which may then be reacted with primary or secondary amines in thepresence of a coupling reagent such asN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) to give compounds of formula 4.

According to Scheme 10, compound 1 can be reacted with an α-haloamide inthe presence of a base such as cesium carbonate and subsequentlydeprotected under aqueous acidic conditions to give compounds of type 2.Compounds of type 2 can be reacted with either primary or secondaryamines under reductive conditions to give compounds of type 4 and 3respectively, using a reeducating agent for example sodiumtriacetoxyborohydride. Intermediate 3 can be further elaborated byreaction with aldehydes in the presence of an appropriate reducing agentsuch as sodium triacetoxyborohydride to give compounds 4.

Pyrazole compounds of the formula 1 may be elaborated via a coppercatalyzed coupling with for example a phenyl iodide containing asecondary or tertiary amine sidechain to afford compound 2.

Treatment of compound 3 with thiourea in an appropriate solvent such asethanol with heating provides thiazole compound 4. Aminothiazole 4 canbe converted to the bromide 5 by treatment with tBuONO, CuBr₂ in asuitable solvent, for example acetonitrile. Subsequent hydrolysis ofcompound 5 using an aqueous base such as potassium hydroxide in acompatible solvent like ethanol will afford acid (6). Compound 7 can beprepared by treatment of compound 6 with diphenylphosphoryl azide (DPPA)in tert-butanol followed by deprotection under acidic conditions.Activation of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid with thionylchloride in a solvent such as THF in the presence of a base like DIPEAand susquent reaction with 7 to give compound 8. Demethylation of arylmethylether 8 with for example BBr₃ in DCM followed by alkylation withsodium chlorodifluoroacetate and an appropriate base and solventcombination such as cesium carbonate in DMF will give compound 10.

Alternatively compounds of Formula 6 can be synthesized as shown inReaction Scheme 13. For example, compounds 1 can be prepared bytreatment of commercially available substituted acetophenones withdiethyl carbonate and subsequent bromination using for example brominein dioxane. Treatment of compounds 1 with a suitably substitutedthioamide or thiourea provides thiazole compounds 2. Compounds 2 can behydrolysed using an aqueous base such as potassium hydroxide in acompatible solvent such as THF to afford acid compounds 35. Compounds 4can be prepared by treatment of compounds 3 with diphenylphosphorylazide (DPPA) in tert-butanol. Deprotection of compounds 4 under acidicconditions provides amino compounds 5. Compounds of formula 6 canprepared by treatment of compounds 5 withpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride in pyridine.

Compounds of type 1 can be reacted with suitable nucleophiles such asappropriately mono-substituted cyclic diamines, acetal containing cyclicamines and cyclic amines containing a substituted second amino group canbe achieved with heating in a solvent such as DMA to give compounds 7, 2and 6 respectively. Compounds of type 2 can be deprotected under aqueousacidic conditions to provide structures of type 3. Compounds 3 can bereductively aminated with mono or di-substituted amines, with regards tothe mono substituted amino products they can be further elaborated via areductively alkylated with a suitable aldehyde in the presence of areducing agent such as sodium cyanoborohydride giving compounds of type5.

Compound 1 can undergo a Sonogashria reaction with an N-substitutedpropargyl amine or propargyl alcohol to give compounds 2 and 3respectively in the presence of a palladium source, a copper (i) halideand base in an appropriate solvent with heating. For example, this couldbe a combination of Pd(PPh₃)₂Cl₂, Cu(I)I, Et₃N in THF. Alcohol 3 can beconverted to the bromide 4 with CBr₄, PPh₃ in a suitable solvent such asDCM. The bromide can be then displaced with primary and secondary aminesgiving structures of type 5.

As shown in Scheme 16, compounds of type 1 can be reacted with1,2-dibromo ethane to give alkyl bromides 2. Reaction of 2 with aminenucleophiles can produce structures of type 4.

As shown in Scheme 17, compounds of type 1 can be alkylated with aminecontaining electrophiles to produce compounds 2. Manipulation offunctional groups on the pendant amine can produce structures of type 3and 4.

As shown in Scheme 18, compounds of type 1 can be reacted with allylicdihalides to produce compounds 2. Further reaction of the pendantallylic halide with amine nucleophiles can produce structures of type 4.

As shown in Scheme 19, compounds of type 1 can be reacted withsubstituted piperazines and an appropriate dehydrating agent (such asHATU) to produce structures of type 4. Alternatively, compounds of type1 can be coupled with appropriately mono-protected piperazines toproduce compounds 2. Compounds 2 can then be deprotected and furtherreacted with appropriate electrophiles to produce structures of type 4.

As shown in Scheme 20, compounds of type 1 can be reacted with epoxidesin the presence of a Lewis acid such as Yb(OTf)₃ to produce structuressuch as 2 and 3. Deprotection can then produce structures of type 4 and5.

As shown in Scheme 21, compounds of type 1 can be reacted with epoxidesin the presence of a Lewis acid such as Yb(OTf)₃ to produce structuressuch as 2. The resulting alcohol can then be oxidized to producestructures of type 3.

As shown in Scheme 22, reaction of compounds of type 1 with appropriateelectrophiles in the presence of base, followed by deprotection canproduce structures such as 2. Further manipulation of the reactive aminecan then produce structures of type 3.

As shown in Scheme 23, reaction of compounds of type 1 with propargylbromide or chloride in the presence of a base can produce compounds oftype 2. Reaction of 2 with azide compounds such as 3 in the presence ofa copper halide and organic base, followed by deprotection can lead totriazole compounds of type 4. Further manipulation of the reactive aminecan then produce structures of type 5.

As shown in Scheme 24, reaction of compounds of type 1 with a2-(halomethyl)oxirane can produce compounds of type 2. Reaction ofcompounds of type 2 with nucleophilic amines can lead to compounds oftype 3. Oxidation of 3 leads to compounds of type 4.

As shown in Scheme 25, reaction of compounds of type 1 with appropriateallylic alkylating reagents in the presense of base leads to compoundsof type 2. Deprotection of the amino protecting group under acidicconditions, followed by reductive amination or alkylation of thereactive amine leads to compounds of type 3.

As shown in Scheme 26, reaction of compounds of type 1 with appropriateallylic alkylating reagents leads to compounds of type 2. Removal of theketal protecting group under acidic conditions, followed by reaction ofthe liberated ketone with an amine under reductive amination conditionsleads to compounds of type 3. A subsequent reductive amination oralkylation step produces structures of type 3.

It will be appreciated that where appropriate functional groups exist,compounds of various formulae or any intermediates used in theirpreparation may be further derivatised by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCO′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O—(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R″ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g. tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, atan appropriate temperature, for example from about −78° C. to the refluxtemperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent known to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalused hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e —CO₂H to —CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g. —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxygroup using conditions known to those skilled in the art. For example,an alcohol may be reacted with thioyl chloride in a halogenatedhydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.A base (e.g. triethylamine) may also be used in the reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g. sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g. palladium orcopper) catalysed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

Methods of Separation

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another or from starting materials. Thedesired products of each step or series of steps is separated orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization or trituration from a solvent orsolvent mixture, distillation, sublimation, or chromatography.Chromatography can involve any number of methods including, for example:reverse-phase and normal phase; size exclusion; ion exchange;supercritical fluid; high, medium, and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. Example separation methods include boilingpoint, and molecular weight in distillation and sublimation, presence orabsence of polar functional groups in chromatography, stability ofmaterials in acidic and basic media in multiphase extraction, and thelike. One skilled in the art will apply techniques most likely toachieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn or supercritical fluid chromatography.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111,incorporated herein by reference). By method (3), a racemic mixture oftwo enantiomers can be separated by chromatography using a chiralstationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapmanand Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378(1990)). Enriched or purified enantiomers can be distinguished bymethods used to distinguish other chiral molecules with asymmetriccarbon atoms, such as optical rotation and circular dichroism. Theabsolute stereochemistry of chiral centers and enatiomers can bedetermined by x-ray crystallography.

Positional isomers, for example E and Z forms, of compounds of Formula(00A), (OA), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), and intermediates for their synthesis, may beobserved by characterization methods such as NMR and analytical HPLC.For certain compounds where the energy barrier for interconversion issufficiently high, the E and Z isomers may be separated, for example bypreparatory HPLC.

Pharmaceutical Compositions and Administration

The compounds with which the invention is concerned are JAK kinaseinhibitors, such as JAK1 inhibitors, and are useful in the treatment ofseveral diseases, for example, inflammatory diseases, such as asthma.

Accordingly, another embodiment provides pharmaceutical compositions ormedicaments containing a compound of the invention, such as a compoundof Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or a compound of Table 1 or of Examples1-468, and a pharmaceutically acceptable carrier, diluent or excipient,as well as methods of using the compounds of the invention to preparesuch compositions and medicaments.

In one example, a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, buttypically ranges anywhere from about 3 to about 8. In one example, acompound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or ofExamples 1-468, is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of the present invention, such as a compoundof Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or a compound of Table 1 or of Examples1-468, are sterile. The compound may be stored, for example, as a solidor amorphous composition, as a lyophilized formulation or as an aqueoussolution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 g to about 1 mg per kg body weight of a human, preferably 0.1 g to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

The compounds of the invention, such as a compound of Formula (00A),(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X), or a compound of Table 1 or of Examples 1-468, may beadministered by any suitable means, including oral, topical (includingbuccal and sublingual), rectal, vaginal, transdermal, parenteral,subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal,inhaled and epidural and intranasal, and, if desired for localtreatment, intralesional administration.

Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration. In some embodiments,inhaled administration is employed.

The compounds of the present invention, such as a compound of Formula(00A), (OA), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468, maybe administered in any convenient administrative form, e.g., tablets,powders, capsules, lozenges, granules, solutions, dispersions,suspensions, syrups, sprays, vapors, suppositories, gels, emulsions,patches, etc. Such compositions may contain components conventional inpharmaceutical preparations, e.g., diluents (e.g., glucose, lactose ormannitol), carriers, pH modifiers, buffers, sweeteners, bulking agents,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, perfuming agents,flavoring agents, other known additives as well as further activeagents.

Suitable carriers and excipients are well known to those skilled in theart and are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Forexample, carriers include solvents, dispersion media, coatings,surfactants, antioxidants, preservatives (e.g., antibacterial agents,antifungal agents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, gels, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, pp 1289-1329, 1990). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.Exemplary excipients include dicalcium phosphate, mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate or combinations thereof. A pharmaceutical composition maycomprise different types of carriers or excipients depending on whetherit is to be administered in solid, liquid or aerosol form, and whetherit need to be sterile for such routes of administration.

For example, tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers, for example, lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example, magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample, methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavoring or coloring agents.

For topical application to the skin, a compound may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

Compounds of the invention, such as a compound of Formula (00A), (0A),(A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or(X), or a compound of Table 1 or of Examples 1-468, may also beformulated for inhalation, for example, as a nasal spray, or dry powderor aerosol inhalers. For delivery by inhalation, the compound istypically in the form of microparticles, which can be prepared by avariety of techniques, including spray-drying, freeze-drying andmicronisation. Aerosol generation can be carried out using, for example,pressure-driven jet atomizers or ultrasonic atomizers, such as by usingpropellant-driven metered aerosols or propellant-free administration ofmicronized compounds from, for example, inhalation capsules or other“dry powder” delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebulizer or as an aerosol in a liquidpropellant, for example, for use in a pressurized metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂) andHFA-152 (CH₄F₂ and isobutane).

In some embodiments, a composition of the invention is in dry powderform, for delivery using a dry powder inhaler (DPI). Many types of DPIare known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of, for example, greater than 90 am.

In the case of an aerosol-based formulation, an example is:

Compound of the invention* 24 mg/canister Lecithin, NF Liq. Conc. 1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister. *Such as a compound ofFormula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or a compound of Table 1 or of Examples1-468.

A compound, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, may be dosed as described depending onthe inhaler system used. In addition to the compound, the administrationforms may additionally contain excipients as described above, or, forexample, propellants (e.g., Frigen in the case of metered aerosols),surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers (e.g., lactose in the case of powder inhalers) or,if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g., Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inthe case of powder inhalers in particular, a number of technicalsolutions are available (e.g., Diskhaler®, Rotadisk®, Turbohaler® or theinhalers, for example, as described in U.S. Pat. No. 5,263,475,incorporated herein by reference). Additionally, compounds of theinvention, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, may be delivered in multi-chamberdevices thus allowing for delivery of combination agents.

The compound, such as a compound of Formula (00A), (0A), (A), (Ia),(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or acompound of Table 1 or of Examples 1-468, may also be administeredparenterally in a sterile medium. Depending on the vehicle andconcentration used, the compound can either be suspended or dissolved inthe vehicle. Advantageously, adjuvants such as a local anaesthetic,preservative or buffering agents can be dissolved in the vehicle.

Targeted Inhaled Drug Delivery

Optimisation of drugs for delivery to the lung by topical (inhaled)administration has been recently reviewed (Cooper, A. E. et al. Curr.Drug Metab. 2012, 13, 457-473). Due to limitations in the deliverydevice, the dose of an inhaled drug is likely to be low (approximately<1 mg/day) in humans which necessitates highly potent molecules. Forcompounds destined to be delivered via dry powder inhalation there isalso a requirement to be able to generate crystalline forms of thecompound that can be micronized to 1-5 m in size. Additionally, thecompound needs to maintain a sufficient concentration in the lung over agiven time period so as to be able to exert a pharmacological effect ofthe desired duration, and for pharmacological targets where systemicinhibition of said target is undesired, to have a low systemic exposure.The lung has an inherently high permeability to both large molecules(proteins, peptides) as well as small molecules with concomitant shortlung half-lives, thus it is necessary to attenuate the lung absorptionrate through modification of one or more features of the compounds:minimizing membrane permeability, reducing dissolution rate, orintroducing a degree of basicity into the compound to enhance binding tothe phospholipid-rich lung tissue or through trapping in acidicsub-cellular compartments such as lysosomes (pH 5). Accordingly, in someembodiments, compounds of the present invention exhibit one or more ofthese features.

Matched Pair Analysis

FIG. 1 depicts a matched pair analysis of certain compounds of thepresent invention containing either an OMe (i) or OCHF₂ (ii) group atthe indicated position. Any two dots joined by a line represent twocompounds with identical R₁ and R₂ groups, and differing only by an OMeor OCHF₂ substitution at the indicated position. FIG. 1 demonstratesthat OCHF₂ substituted analogs (ii) are consistently more potent in theJAK1 biochemical assay (described below) than the corresponding OMeanalogs (i).

Methods of Treatment with and Uses of Janus Kinase Inhibitors

The compounds of the present invention, such as a compound of Formula(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468,inhibit the activity of a Janus kinase, such as JAK1 kinase. Forexample, a compound of the present invention, such as a compound ofFormula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), or (X), or a compound of Table 1 or of Examples1-468, inhibits the phosphorylation of signal transducers and activatorsof transcription (STATs) by JAK1 kinase as well as STAT mediatedcytokine production. Compounds of the present invention, such as acompound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or ofExamples 1-468, are useful for inhibiting JAK1 kinase activity in cellsthrough cytokine pathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9,IL-10, IL-13, IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma pathways.Accordingly, in one embodiment is provided a method of contacting a cellwith a compound of the present invention, such as a compound of Formula(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468, toinhibit a Janus kinase activity in the cell (e.g., JAK1 activity). Thecompounds of the present invention, such as compounds of Formula (00A),(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X), or a compound of Table 1 or of Examples 1-468, can be usedfor the treatment of immunological disorders driven by aberrant IL-6,IL-15, IL-7, IL-2, IL-4, IL9, IL-10, IL-13, IL-21, G-CSF, IFNalpha,IFNbeta or IFNgamma cytokine signaling.

Accordingly, one embodiment includes compounds of of the presentinvention, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, for use in therapy.

In some embodiments, there is provided use a compound of the presentinvention, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, in the treatment of an inflammatorydisease. Further provided is use of a compound of the present invention,such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1or of Examples 1-468, for the preparation of a medicament for thetreatment of an inflammatory disease, such as asthma. Also provided is acompound of the present invention, such as a compound of Formula (00A),(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X), or a compound of Table 1 or of Examples 1-468, for use inthe treatment of an inflammatory disease, such as asthma.

Another embodiment includes a method of preventing, treating orlessening the severity of a disease or condition, such as asthma,responsive to the inhibition of a Janus kinase activity, such as JAK1kinase activity, in a patient. The method can include the step ofadministering to a patient a therapeutically effective amount of acompound of the present invention, such as a compound of Formula (00A),(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), or (X), or a compound of Table 1 or of Examples 1-468. In oneembodiment, the disease or condition responsive to the inhibition of aJanus kinase, such as JAK1 kinase, is asthma.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation (e.g., transplant rejection),immunodeficiency disorders, destructive bone disorders, proliferativedisorders, infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorders or amyeloproliferative disorder.

In one embodiment, the inflammatory disease is rheumatoid arthritis,psoriasis, asthma, inflammatory bowel disease, contact dermatitis ordelayed hypersensitivity reactions. In one embodiment, the autoimmunedisease is rheumatoid arthritis, lupus or multiple sclerosis.

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the disease is a myeloproliferative disorder. In oneembodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

Another embodiment includes the use of a compound of the presentinvention, such as a compound of Formula (00A), (0A), (A), (Ia), (Ib),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compoundof Table 1 or of Examples 1-468, for the manufacture of a medicament forthe treatment of a disease described herein (e.g., an inflammatorydisorder, an immunological disorder or cancer). In one embodiment, theinvention provides a method of treating a disease or condition asdescribed herein e.g., an inflammatory disorder, an immunologicaldisorder or cancer) by targeting inhibition of a JAK kinase, such asJAK1.

Combination Therapy

The compounds of the present invention, such as a compound of Formula(00A), (OA), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468, maybe employed alone or in combination with other agents for treatment. Thesecond compound of a pharmaceutical composition or dosing regimentypically has complementary activities to the compound of this inventionsuch that they do not adversely affect each other. Such agents aresuitably present in combination in amounts that are effective for thepurpose intended. The compounds may be administered together in aunitary pharmaceutical composition or separately and, when administeredseparately this may occur simultaneously or sequentially. Suchsequential administration may be close or remote in time.

For example, other compounds may be combined with compounds with whichthe invention is concerned for the prevention or treatment ofinflammatory diseases, such as asthma. Thus the present invention isalso concerned with pharmaceutical compositions comprising atherapeutically effective amount of a compound of the invention and oneor more other therapeutic agents. Suitable therapeutic agents for acombination therapy with compounds of the invention include, but are notlimited to: an adenosine A2A receptor antagonist; an anti-infective; anon-steroidal Glucocorticoid Receptor (GR Receptor) agonist; anantioxidant; a β2 adrenoceptor agonist; a CCR1 antagonist; a chemokineantagonist (not CCR1); a corticosteroid; a CRTh2 antagonist; a DP1antagonist; a formyl peptide receptor antagonist; a histone deacetylaseactivator; a chloride channel hCLCA1 blocker; an epithelial sodiumchannel blocker (ENAC blocker; an inter-cellular adhesion molecule 1blocker (ICAM blocker); an IKK2 inhibitor; a JNK inhibitor; acyclooxygenase inhibitor (COX inhibitor); a lipoxygenase inhibitor; aleukotriene receptor antagonist; a dual β2 adrenoceptor agonist/M3receptor antagonist (MABA compound); a MEK-1 inhibitor; amyeloperoxidase inhibitor (MPO inhibitor); a muscarinic antagonist; ap38 MAPK inhibitor; a phosphodiesterase PDE4 inhibitor; aphosphatidylinositol 3-kinase δ inhibitor (PI3-kinase δ inhibitor); aphosphatidylinositol 3-kinase γ inhibitor (PI3-kinase γ inhibitor); aperoxisome proliferator activated receptor agonist (PPARγ agonist); aprotease inhibitor; a retinoic acid receptor modulator (RAR γmodulator); a statin; a thromboxane antagonist; a TLR7 receptor agonist;or a vasodilator.

In addition, compounds of the invention, such as a compound of Formula(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), or (X), or a compound of Table 1 or of Examples 1-468, maybe combined with: (1) corticosteroids, such as alclometasonedipropionate, amelometasone, beclomethasone dipropionate, budesonide,butixocort propionate, biclesonide, blobetasol propionate,desisobutyrylciclesonide, dexamethasone, dtiprednol dicloacetate,fluocinolone acetonide, fluticasone furoate, fluticasone propionate,loteprednol etabonate (topical) or mometasone furoate; (2)β2-adrenoreceptor agonists such as salbutamol, albuterol, terbutaline,fenoterol, bitolterol, carbuterol, clenbuterol, pirbuterol, rimoterol,terbutaline, tretoquinol, tulobuterol and long acting β2-adrenoreceptoragonists such as metaproterenol, isoproterenol, isoprenaline,salmeterol, indacaterol, formoterol (including formoterol fumarate),arformoterol, carmoterol, abediterol, vilanterol trifenate, olodaterol;(3) corticosteroid/long acting β2 agonist combination products such assalmeterol/fluticasone propionate (Advair®, also sold as Seretide®),formoterol/budesonide (Symbicort®), formoterol/fluticasone propionate(Flutiform®), formoterol/ciclesonide, formoterol/mometasone furoate,indacaterol/mometasone furoate, vilanterol trifenate/fluticasonefuroate, or arformoterol/ciclesonide; (4) anticholinergic agents, forexample, muscarinic-3 (M3) receptor antagonists such as ipratropiumbromide, tiotropium bromide, aclidinium (LAS-34273), glycopyrroniumbromide, umeclidinium bromide; (5) M3-anticholinergic/β2-adrenoreceptoragonist combination products such as vilanterol/umeclidinium (Anoro®Ellipta®), olodaterol/tiotropium bromide, glycopyrroniumbromide/indacaterol (Ultibro®, also sold as Xoterna®), fenoterolhydrobromide/ipratropium bromide (Berodual®), albuterolsulfate/ipratropium bromide (Combivent®), formoterolfumarate/glycopyrrolate, or aclidinium bromide/formoterol (6) dualpharmacology M3-anticholinergic/β2-adrenoreceptor agonists such asbatefenterol succinate, AZD-2115 or LAS-190792; (7) leukotrienemodulators, for example, leukotriene antagonists such as montelukast,zafirulast or pranlukast or leukotriene biosynthesis inhibitors such aszileuton, or LTB4 antagonists such as amelubant, or FLAP inhibitors suchas fiboflapon, GSK-2190915; (8) phosphodiesterase-IV (PDE-IV) inhibitors(oral or inhaled), such as roflumilast, cilomilast, oglemilast,rolipram, tetomilast, AVE-8112, revamilast, CHF 6001; (9)antihistamines, for example, selective histamine-1 (H1) receptorantagonists such as fexofenadine, citirizine, loratidine or astemizoleor dual H1/H3 receptor antagonists such as GSK 835726, or GSK 1004723;(10) antitussive agents, such as codeine or dextramorphan; (11) amucolytic, for example, N-acetyl cysteine or fudostein; (12) aexpectorant/mucokinetic modulator, for example, ambroxol, hypertonicsolutions (e.g., saline or mannitol) or surfactant; (13) a peptidemucolytic, for example, recombinant human deoxyribonoclease I(dornase-alpha and rhDNase) or helicidin; (14) antibiotics, for exampleazithromycin, tobramycin or aztreonam; (15) non-selective COX-1/COX-2inhibitors, such as ibuprofen or ketoprofen; (16) COX-2 inhibitors, suchas celecoxib and rofecoxib; (17) VLA-4 antagonists, such as thosedescribed in WO97/03094 and WO97/02289, each incorporated herein byreference; (18) TACE inhibitors and TNF-c inhibitors, for exampleanti-TNF monoclonal antibodies, such as Remicade® and CDP-870 and TNFreceptor immunoglobulin molecules, such as Enbrel®; (19) inhibitors ofmatrix metalloprotease, for example MMP-12; (20) human neutrophilelastase inhibitors, such as BAY-85-8501 or those described inWO2005/026124, WO2003/053930 and WO06/082412, each incorporated hereinby reference; (21) A2b antagonists such as those described inWO2002/42298, incorporated herein by reference; (22) modulators ofchemokine receptor function, for example antagonists of CCR3 and CCR8;(23) compounds which modulate the action of other prostanoid receptors,for example, a thromboxane A₂ antagonist; DP1 antagonists such aslaropiprant or asapiprant CRTH2 antagonists such as OC000459,fevipiprant, ADC 3680 or ARRY 502; (24) PPAR agonists including PPARalpha agonists (such as fenofibrate), PPAR delta agonists, PPAR gammaagonists such as pioglitazone, rosiglitazone and balaglitazone; (25)methylxanthines such as theophylline or aminophylline andmethylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate andtheophylline/beclometasone dipropionate; (26) A2a agonists such as thosedescribed in EP1052264 and EP1241176; (27) CXCR2 or IL-8 antagonistssuch as AZD-5069, AZD-4721, danirixin; (28) IL-R signalling modulatorssuch as kineret and ACZ 885; (29) MCP-1 antagonists such as ABN-912;(30) a p38 MAPK inhibitor such as BCT197, JNJ49095397, losmapimod orPH-797804; (31) TLR7 receptor agonists such as AZD 8848; (32) PI3-kinaseinhibitors such as RV1729 or GSK2269557.

In some embodiments, the compounds of the present invention, such as acompound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or ofExamples 1-468, can be used in combination with one or more additionaldrugs, for example anti-hyperproliferative, anti-cancer, cytostatic,cytotoxic, anti-inflammatory or chemotherapeutic agents, such as thoseagents disclosed in U.S. Publ. Appl. No. 2010/0048557, incorporatedherein by reference. A compound of the present invention, such as acompound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or ofExamples 1-468, can be also used in combination with radiation therapyor surgery, as is known in the art.

Articles of Manufacture Another embodiment includes an article ofmanufacture (e.g., a kit) for treating a disease or disorder responsiveto the inhibition of a Janus kinase, such as a JAK1 kinase. The kit cancomprise:

(a) a first pharmaceutical composition comprising a compound of thepresent invention, such as a compound of Formula (00A), (0A), (A), (Ia),(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or acompound of Table 1 or of Examples 1-468; and

(b) instructions for use.

In another embodiment, the kit further comprises:

(c) a second pharmaceutical composition, such as a pharmacueitcalcomposition comprising an agent for treatment as described above, suchas an agent for treatment of an inflammatory disorder, or achemotherapeutic agent.

In one embodiment, the instructions describe the simultaneous,sequential or separate administration of said first and secondpharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers. In another embodiment, the first and secondcompositions are contained in the same container.

Containers for use include, for example, bottles, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofthe present invention, such as a compound of Formula (00A), (0A), (A),(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X),or a compound of Table 1 or of Examples 1-468, or composition thereof,which is effective for treating the condition and may have a sterileaccess port (for example the container may be an intravenous solutionbag or a vial having a stopper pierceable by a hypodermic injectionneedle). The label or package insert indicates that the compound orcomposition is used for treating the condition of choice, such as asthmaor cancer. In one embodiment, the label or package inserts indicatesthat the compound or composition can be used to treat a disorder. Inaddition, the label or package insert may indicate that the patient tobe treated is one having a disorder characterized by overactive orirregular Janus kinase activity, such as overactive or irregular JAK1activity. The label or package insert may also indicate that thecompound or composition can be used to treat other disorders.

Alternatively, or additionally, the kit may further comprise a second(or third) container comprising a pharmaceutically acceptable buffer,such as bacteriostatic water for injection (BWFI), phosphate-bufferedsaline, Ringer's solution or dextrose solution. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of the present invention, and alternative methods forpreparing the compounds are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

EXAMPLES

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

General Experimental Details

All solvents and commercial reagents were used as received unlessotherwise stated. Where products were purified by chromatography onsilica this was carried out using either a glass column manually packedwith silica gel (Kieselgel 60, 220-440 mesh, 35-75 μm) or an Isolute®SPE Si II cartridge. ‘Isolute SPE Si cartridge’ refers to a pre-packedpolypropylene column containing unbonded activated silica with irregularparticles with average size of 50 μm and nominal 60A porosity. Where anIsolute® SCX-2 cartridge was used, ‘Isolute® SCX-2 cartridge’ refers toa pre-packed polypropylene column containing a non-end-cappedpropylsulphonic acid functionalised silica strong cation exchangesorbent.

Preparative HPLC Conditions

HPLC System 1: C18-reverse-phase column (250×21.2 mm Gemini column with5 μm particle size), eluting with a gradient of A: water+0.1% formicacid; B: acetonitrile+0.1% formic acid with a flow rate typically 20mL/min and a gradient increasing in B. UV detection at 254 nm. Compoundswere obtained as the formate salt where stated.HPLC System 2: Phenylhexyl reverse-phase column (250×21.2 mm Geminicolumn with 5 μm particle size), eluting with a gradient of A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid with a flowrate typically 20 mL/min and gradient of 1%/min increasing in B. UVdetection at 254 nm. Compounds were obtained as the formate salt wherestated.HPLC System 3: C18-reverse-phase end-capped column (250×21.2 mm Geminicolumn with 5 m particle size), eluting with a gradient of A: water+0.1%ammonia; B: acetonitrile+0.1% ammonia with a flow rate typically 20mL/min and a gradient increasing in B. UV detection at 254 nm. Compoundswere obtained as the free base.

NMR Analytical Methods

¹H NMR spectra were recorded at ambient temperature using one of thefollowing:

-   -   i. Varian Unity Inova (400 MHz) spectrometer with a 400 4NUC 5        mm probe.    -   ii. Bruker Avance DRX400 (400 MHz) spectrometer with a PABBO 5        mm probe.    -   iii. Varian Unity Inova (400 MHz) spectrometer with a 5 mm        inverse detection triple resonance probe.    -   iv. Bruker Avance DRX (400 MHz) spectrometer with a 5 mm inverse        detection triple resonance TXI probe.

Chemical Shifts are Expressed in Ppm Relative to Tetramethylsilane.

LC-MS Analytical Methods

LC-MS information is provided in Table 2.

LC-MS Method 1: Waters Platform LC with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 m particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (100 μl split to MS with in-line UV detector)

MS ionisation method—Electrospray (positive and negative ion)

LC-MS Method 2: Waters Micromass ZMD with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (100 μl split to MS with in-line UV detector)

MS ionisation method—Electrospray (positive and negative ion)

LC-MS Method 3: VG Platform II quadrupole spectrometer with aC18-reverse-phase column (30×4.6 mm Phenomenex Luna 3 m particle size),elution with A: water+0.1% formic acid; B: acetonitrile+0.1% formicacid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μl/min split to the ESI source with inlineHP1050 DAD detection)

MS ionisation method—Electrospray (positive and negative ion)

LC-MS Method 4: Finnigan AQA with a C18-reverse-phase column (30×4.6 mm)Phenomenex Luna 3 μm particle size), elution with A: water+0.1% formicacid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV

MS ionisation method—Electrospray (positive ion)

LC-MS Method 5: Waters Micromass ZQ2000 quadrupole mass spectrometerwith a C18-reverse-phase column (100×2.1 mm Acquity BEH C18 1.7μ,Acquity BEH Shield RP18 1.7μ, or Acquity HSST3 1.8μ) maintained at 40°C., elution with A: water+0.1% formic acid; B: acetonitrile+0.1% formicacid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.45 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Detection—MS, UV PDA

MS ionisation method—Electrospray (positive ion)

LC-MS Method 6: Waters Acquity UPLC with a C18-reverse-phase column(100×2.1 mm Acquity BEH C18, 1.7 μm particle size), elution with solventA: water+0.1% formic acid; solvent B: acetonitrile+0.1% formic acid at40° C. Gradient:

Gradient - Time flow mL/min % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.45 95 6.80 0.4 5 95 8.00 0.4 95 5

Detection—UV (220 nm)

MS ionisation method—ESI⁺

LC-MS Method 7: SHIMADZU 20A HPLC with a C18-reverse-phase column(30×2.1 mm Xtimate TM-C18, 3 m particle size), elution with solvent A:water+0.038% trifluoroacetic acid; solvent B: acetonitrile+0.02%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 1.2 90 10 0.90 1.2 20 80 1.51.2 20 80 2.0 1.2 90 10

Detection—UV (220 nm)

MS ionisation method—ESI⁺

LC-MS Method 8: SHIMADZU 20A HPLC with a C18-reverse-phase column(30×2.1 mm Xtimate TM-C18, 3 μm particle size), elution with solvent A:water+0.038% trifluoroacetic acid; solvent B: acetonitrile+0.02%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 1.2 90 10 1.35 1.2 20 80 2.251.2 20 80 2.75 1.2 90 10

Detection—UV (220 nm)

MS ionisation method—ESI⁺

LC-MS Method 9: SHIMADZU 20A HPLC with a C18-reverse-phase column(30×2.1 mm Xtimate TM-C18, 3 μm particle size), elution with solvent A:water+0.038% trifluoroacetic acid; solvent B: acetonitrile+0.02%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 1.2 100 0 0.90 1.2 40 60 1.51.2 40 60 2.0 1.2 100 0

Detection—UV (220 nm)

MS ionisation method—ESI⁺

LC-MS Method 10: SHIMADZU 20A HPLC with a C18-reverse-phase column(30×2.1 mm Xtimate TM-C18, 3 m particle size), elution with solvent A:water+0.038% trifluoroacetic acid; solvent B: acetonitrile+0.02%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 0.8 100 0 6.0 0.8 40 60 6.5 0.840 60 7.0 0.8 100 0

Detection—UV (220 nm)

MS ionisation method—ESI⁺

LC-MS Method 11: Agilent 1200 HPLC with an Xtimate C18 column (3 μm,30×2.1 mm), elution with A: water+0.038% trifluoroacetic acid; B:acetonitrile+0.02% trifluoroacetic acid.

Gradient - Time flow mL/min % A % B 0.00 1.2 90 10 0.90 1.2 20 80 1.501.2 90 10 2.00 1.2 90 10

Detection—MS, UV (PDA detector)

MS ionisation method—Electrospray (positive ion)

LC-MS Method 12: Agilent 1200 HPLC with an Xtimate C18 column (3 um,30×2.1 mm), elution with A: water+0.038% trifluoroacetic acid; B:acetonitrile+0.02% trifluoroacetic acid.

Gradient - Time flow mL/min % A % B 0.00 1.2 100 0 0.90 1.2 40 60 1.501.2 100 0 2.00 1.2 100 0

Detection—MS, UV (PDA detector)

MS ionisation method—Electrospray (positive ion)

LC-MS Method 13: Agilent 1200 HPLC with an Xtimate C18 column (3 um,30×2.1 mm), elution with A: water+0.038% trifluoroacetic acid; B:acetonitrile+0.02% trifluoroacetic acid.

Gradient - Time flow mL/min % A % B 0.00 0.8 100 0 1.35 0.8 40 60 2.250.8 100 0 3.00 0.8 100 0

Detection—MS, UV (PDA detector)

MS ionisation method—Electrospray (positive ion)

LC-MS Method 14: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×2.0 mm Shim-pack XR-ODS, 1.6 m particle size), elution with solventA: water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.01 0.7 90 10 2.20 0.7 0 100 3.200.7 0 100 3.30 0.7 90 10

Detection—UV (254 nm)

MS ionisation method—ESI⁺

LC-MS Method 15: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm Shim-pack XR-ODS, 1.6 m particle size), elution with solventA: water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.01 1.0 95 5 3.00 1.0 20 80 3.801.0 20 80 3.90 1.0 95 5

Detection—UV (254 nm)

MS ionisation method—ESI⁺

LC-MS Method 16: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm Shim-pack XR-ODS, 2.2 m particle size), elution with solventA: water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.01 1.0 95 5 4.20 1.0 25 75 5.201.0 25 75 5.30 1.0 95 5

Detection—UV (254 nm)

MS ionisation method—ESI⁺

LC-MS Method 17: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm Shim-pack XR-ODS, 2.2 m particle size), elution with solventA: water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.01 1.0 95 5 2.20 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (254 nm)

MS ionisation method—ESI⁺

LC-MS Method 18: SHIMADZU LCMS-2020 HPLC column (150×4.6 mm Venusil XBPSilica, 5.0 μm particle size), elution with solvent A: Hexane; solventB:Ethanol.

Gradient - Time flow mL/min % A % B 0.01 1.0 80 20 6.00 1.0 0 100 12.01.0 0 100

Detection—UV (254 nm)

MS ionisation method—ESI⁺

LC-MS Method 19: SHIMADZU 20A HPLC with a C18-reverse-phase column (50×3mm Xtimate TM —C18, 2.2 μm particle size), elution with solvent A:water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.101.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 20: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3 mm Xtimate TM-C18, 2.2 μm particle size), elution with solvent A:water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 21: SHIMADZU 20A HPLC with a C18-reverse-phase column (50×3mm Xtimate TM-C18, 2.2 μm particle size), elution with solvent A:water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 22: SHIMADZU 20A HPLC with a C18-reverse-phase column (50×3mm Xtimate TM-C18, 2.2 μm particle size), elution with solvent A:water+0.05% formic acid; solvent B: acetonitrile+0.05% formic acid.Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 1.20 1.0 0 100 2.201.0 0 100 2.30 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 23: SHIMADZU 20A HPLC with a C18-reverse-phase column (50×3mm Xtimate TM-C18, 2.2 μm particle size), elution with solvent A:water+0.1% formic acid; solvent B: acetonitrile+0.05% formic acid.Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.101.0 0 100 3.20 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 24: SHIMADZU 20A HPLC with a C18-reverse-phase column (50×3mm Xtimate TM-C18, 2.2 μm particle size), elution with solvent A:water+0.04% ammonium hydroxide; solvent B: acetonitrile. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 1.20 1.2 0 100 2.201.2 0 100 2.30 1.2 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 25: SHIMADZU 20A HPLC with a C18-reverse-phase column(30×2.1 mm Xtimate TM-C18, 3 μm particle size), elution with solvent A:water+0.05% trifluoroacetic acid; solvent B: acetonitrile+0.05%trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 1.10 1.0 0 100 1.601.0 0 100 1.70 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 26: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm Xtimate TM-C18, 2.6 μm particle size), elution with solventA: Water/0.1% formic acid; solvent B: Acetonitrile/0.1% formic acid.Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.5 90 10 2.00 1.5 0 100 2.701.5 0 100 2.8 1.5 90 10

MS ionization method—Electrospray (positive ion)

LC-MS Method 27: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×2.1 mm Xtimate TM-C18, 2.7 m particle size), elution with solvent A:Water/0.05% formic acid; solvent B: Acetonitrile/0.1% formic acid:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 5 95 2.70 1.05 95 2.8 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Method 28: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm Xtimate TM-C18, 2.5 m particle size), elution with solvent A:Water/5 mM NH₄HCO₃; solvent B: Acetonitrile:

Gradient - Time flow ml/min % A % B 0.00 1.5 90 10 2.10 1.5 5 95 2.701.5 5 95 3.0 1.5 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 29: SHIMADZU LCMS-2020 C18 reverse-phase column (50×3.0mm, Shim-pack XR-ODS, 2.5 μm particle size), elution with solvent A:Water/0.05% TFA₃; solvent B: Acetonitrile/0.05% TFA:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.20 1.0 5 95 3.20 1.05 95 3.30 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 30: SHIMADZU LCMS-2020 C18 reverse-phase column (50×2.1mm, Shiseido CAPCELL CORE C18, 2.7 μm particle size), elution withsolvent A: Water/0.05% TFA₃; solvent B: Acetonitrile/0.05% TFA:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.0 1.0 5 95 2.75 1.05 95 2.80 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 31: SHIMADZU LCMS-2020 C18 reverse-phase column (50×2.1mm, Waters BEH C18, 1.7 μm particle size), elution with solvent A:Water/0.1% TFA₃; solvent B: Acetonitrile/0.1% TFA:

Gradient - Time flow ml/min % A % B 0.00 0.7 90 10 3.50 0.7 5 95 4.600.7 5 95 4.70 0.7 90 10

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 32: SHIMADZU LCMS-2020 C18 reverse-phase column (50×3.0mm, Gemini-NX 3μ C18 110A, 3.0 μm particle size), elution with solventA: Water/6.5 mM NH₄HCO₃ pH10; solvent B: Acetonitrile

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 0.50 1.2 95 5 2.20 1.25 95 3.00 1.2 5 95 3.20 1.2 90 10

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 33: SHIMADZU LCMS-2020 C18 reverse-phase column (50×2.1mm, Waters BEH C18, 1.7 μm particle size), elution with solvent A:Water/0.05% TFA₃; solvent B: Acetonitrile/0.05% TFA:

Gradient - Time flow ml/min % A % B 0.00 0.7 95 5 2.00 0.7 5 95 2.60 0.75 95 2.70 0.7 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 34: SHIMADZU LCMS-2020 C18 reverse-phase column (50×2.1mm, Waters BEH C18, 1.7 μm particle size), elution with solvent A:Water/0.05% TFA₃; solvent B: Acetonitrile/0.05% TFA:

Gradient - Time flow ml/min % A % B 0.00 0.7 95 5 4.00 0.7 20 80 5.000.7 20 80 5.20 0.7 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 35: SHIMADZU LCMS-2020 C18 reverse-phase column (50×3.0mm, Shim-pack XR-ODS, 2.2 μm particle size), elution with solvent A:Water/0.05% TFA₃; solvent B: Acetonitrile/0.05% TFA:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 3.20 1.0 40 60 3.801.0 0 100 4.70 1.0 0 100 4.80 1.0 95 5

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC-MS Methods 36: SHIMADZU 20A HPLC with a C18-reverse-phase column(50×3.0 mm, Gemini-NX 3μ C18 110A, 3.0 μm particle size), elution withsolvent A: Water/5 mM NH₄HCO₃; solvent B: Acetonitrile:

Gradient - Time flow ml/min % A % B 0.00 1.2 90 10 4.00 1.2 40 60 5.201.2 40 60 5.30 1.2 90 10

Detection—UV (220 and 254 nm)

MS ionization method—Electrospray (positive ion)

LC/MS Methods 37: Agilent 10-min LCMS method:

Experiments performed on an Agilent 1100 HPLC coupled with Agilent MSDmass spectrometer using ESI as ionization source. The LC separation wasusing a Phenomenex XB-C18, 1.7 μm, 50×2. 1 mm column with a 0.4ml/minute flow rate. Solvent A is water with 0.1% FA and solvent B isacetonitrile with 0.1% FA. The gradient consisted with 2-98% solvent Bover 7 min and hold 97% B for 1.5 min following equilibration for 1.5min. LC column temperature is 40° C. UV absorbance was collected at 220nm and 254 nm and mass spec full scan was applied to all experiments.

LC/MS Methods 38: Waters 10-min LCMS method:

Experiments performed on a Waters Acquity UPLC with Waters LCT PremierXE mass spectrometer using ESI as ionization source. The LC separationwas using an Acquity UPLC BEH C18, 1.7 um, 2.1×50 mm column and a 0.6ml/minute flow rate. Solvent A is water with 0.050% TFA and solvent B isacetonitrile with 0.05% TFA The gradient consisted of 2-980% solvent Bover 7 min and hold 98% B for 1.5 min following equilibration for 1.5min. LC column temperature is 40° C. UV absorbance was collected at 220nm and 254 nm and mass spec full scan was applied to all experiments.

LC/MIS Methods 39: Shimadzu 5-min LCMS method:

Experiments performed on a Shimadzu LC with LC-30AD solvent pump,SPD-M30A UV detector and 2020 MS using both ESI and APCI as ionizationsource. The LC separation was using a Waters UPLC BEH C18, 1.7 mm,2.1×50 mm column and a 0.7 ml/minute flow rate. Solvent A is water with0.1% FA and solvent B is acetonitrile with 0.1% F A. The gradientconsisted of 2-98% solvent B over 4.5 min and hold 98% B3 for 0.5 minfollowing equilibration for 0.5 min. LC column temperature is 40° C. UVabsorbance was collected at 254 nm and mass spec full scan was appliedto all experiments.

Preparative Mass Directed Automated Purification Conditions

MDAP Method 1: Agilent 1260 infinity purification system. Agilent 6100series single Quadrupole LC/MS. XSEELECT CSH Prep C18 5 μm OBD, 30×150mm, RT. Elution with solvent A: 0.1% aqueous formic acid; solvent B:0.1% formic acid in acetonitrile 60 ml/min. 10%-95%, 22 min, centredaround a specific focused gradient. Injection of a 20-60 mg/ml solutionin DMSO (+optional formic acid and water)

MDAP Method 2: Agilent 1260 infinity purification system. Agilent 6100series single Quadrupole LC/MS. XBridge Prep C18 5 m OBD, 30×150 mm, RT.Elution with solvent A: 0.1% aqueous ammonia; solvent B: 0.1% ammonia inacetonitrile 60 ml/min. 10%-95%, 22 min, centred around a specificfocused gradient. Injection of a 20-60 mg/ml solution in DMSO (+optionalformic acid and water)

Abbreviations

-   -   CH₃OD Deuterated Methanol    -   CDCl₃ Deuterated Chloroform    -   DCM Dichloromethane    -   DIPEA Diisopropylethylamine    -   DMAP 4-Dimethylaminopyridine    -   DMF Dimethylformamide    -   DMSO Dimethylsulfoxide    -   DMSO-d6 Deuterated dimethylsulfoxide    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   HOAc Acetic acid    -   g Gram    -   HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   HCl Hydrochloric acid    -   IMS Industrial methylated spirits    -   L Litre    -   MDAP Mass directed automated purification    -   MeOH Methanol    -   mg Milligram    -   mL Milliliter    -   SCX-2 Strong cation exchange    -   THF Tetrahydrofuran    -   TFA Trifluoroacetic acid

Example A

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide

To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in DMF (25mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesiumcarbonate (10.97 g, 33.67 mmol) and water (2.5 mL). The reaction wasstirred at 100° C. for 16 hours. The reaction mixture was partitionedbetween ethyl acetate and water, the organic portion washed with brine,dried (MgSO₄), and evaporated. The crude product was purified by flashchromatography on silica eluting with 0-20% EtOAc in heptanes to yield2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil(2.98 g, 48%). LCMS (ESI) no m/z signal; ¹H NMR (400 MHz, DMSO-d₆) δ:(ppm) 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).

To a solution of 4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole(preparation described in WO2011003065) (46.5 g, 191 mmol) in DMA (350mL) was added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248mmol), palladium (II) acetate (2.15 g, 9.6 mmol),di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium carbonate(79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6 mmol).

The mixture was degassed with nitrogen for 10 minutes then heated at130° C. for 8 hours. The reaction mixture was allowed to cool to roomtemperature, diluted with ethyl acetate and washed with water and brine,dried (MgSO₄), filtered and evaporated. The resultant crude material waspurified by flash chromatography on silica eluting with 0-10% EtOAc incyclohexane to afford5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole(62.4 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 8.24 (s, 1H), 7.52-7.53(m, 2H), 6.39 (t, 1H), 5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s,9H).

To a solution of5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole(62 g, 148 mmol) in ethanol (600 mL) was added water (200 mL), ammoniumchloride (32 g, 590 mmol) and iron powder (41 g, 740 mmol). The mixturewas heated at 80° C. for 2 hours then allowed to cool to roomtemperature. The residual solid was removed by filtration throughCelite®. The filtrate was evaporated under reduced pressure, dilutedwith water and extracted twice with DCM. The combined organic extractswere washed with water and brine, dried (MgSO₄) and evaporated to afforda dark oil. The oil was purified by flash chromatography on silicaeluting with 0-25% EtOAc in DCM. Appropriate fractions were collectedand the solvent removed in-vacuo to afford5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamineas a brown oil (30.8 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 7.56 (d,1H), 7.44 (dd, 1H), 7.34 (s, 1H), 7.30-7.25 (m, 1H), 6.37 (t, 1H), 5.29(s, 2H), 3.56 (t, 2H), 0.88 (dd, 2H), 0.00 (s, 9H).

A solution of5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine(60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes toan ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonylchloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300mL). On complete addition the mixture was left to stir at roomtemperature for 1 hour. The solvent was evaporated and the residuediluted with 0.5N aqueous HCl and extracted with ethyl acetate. Thecombined organic extract was passed through Celite® to remove theresidual solid and the filtrate washed with 1M aqueous K₂CO₃, water andbrine, dried (Na₂SO₄) and evaporated to give a red solid. The solid wastriturated with 10% diethyl ether in cyclohexane. The solid wascollected by filtration, washed with 1:1 diethyl ether in cyclohexaneand left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amideas an off-white solid (59.2 g, 73%). ¹H NMR (300 MHz, CDCl₃): δ (ppm)9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d,1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t,1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s,9H).

A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide(59.0 g, 110 mmol) in methanol (420 mL) was treated with 6N HCl (80 mL)and the mixture heated at 60° C. for 4 hours. The solvent was evaporatedand the residue triturated with water. The solid was collected byfiltration, washed with water and left to air dry. The solid wastriturated with a minimum volume of acetonitrile, collected byfiltration, washed with diethyl ether and dried at 60° C. under highvacuum to afford the title compound as a yellow solid (42.9 g, 96%). ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.71 (s, 1H), 9.34 (dd, 1H), 8.68-8.69(m, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.62 (dd, 2H), 7.43-7.46 (m, 1H),7.29 (dd, 1H), 7.23 (d, 1H).

Example B

tert-Butyl(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate

To a solution of compound2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(2.78 g, 0.01 mol) in DMF (40 mL) was added DIPEA (3.9 g, 0.03 mol),HATU (3.8 g, 0.01 mol) and5-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-ylamine (2.6 g, 0.01mmol), and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was poured into water and theprecipitate was collected to give the target compound as a solid (4 g,77%). LCMS (Method 7) [M+Na]⁺=541.9, R_(T)=1.20 min. ¹H NMR (400 MHz,DMSO-d₆) δ: (ppm) 13.13 (s, 1H), 9.58 (s, 2H), 9.2 (dd, 1H, J=7.2, 1.6Hz), 8.58 (d, 1H, J=2), 8.27 (s, 1H), 7.60 (m, 2H), 7.23-7.04 (m, 3H),1.48 (s, 9H).

Example C

{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (42.0 g, 104mmol) in DMF (400 mL) was treated with cesium carbonate (37.2 g, 114mmol) and tert-butyl-bromoacetate (22.3 g, 114 mmol) and was left tostir at room temperature for 18 hours. The reaction mixture was dilutedwith water and extracted twice with ethyl acetate. The combined organicextract was washed with water and brine, dried (Na₂SO₄), filtered andevaporated to afford an orange solid. The resultant solid was trituratedwith diethyl ether then recrystallised from acetone to afford a whitesolid (33.2 g, 62%). The mother liquors were combined and evaporated toafford an orange oil. The residual oil was purified by flashchromatography on silica eluting with 0-50% EtOAc in DCM. Appropriatefractions were combined and evaporated to afford a white solid (12.3 g,23%). Combined yield of{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid tert-butyl ester (45.2 g, 85%). LCMS (Method 3) [M+H]⁺=519.1,R_(T)=3.72 min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.86 (s, 1H), 8.75-8.76(m, 2H), 8.56 (dd, 1H), 8.40 (s, 1H), 7.70 (d, 1H), 7.42 (dd, 1H), 6.99(dd, 1H), 6.47 (t, 1H), 4.86 (s, 2H), 1.49 (s, 9H).

To a solution of{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid tert-butyl ester (45.0 g, 86.7 mmol) in dichloromethane (350 mL)was added TFA (100 mL) and the mixture left to stir at room temperaturefor 18 hours. The solvent was evaporated and the resultant residuetriturated with diethyl ether. The resultant solid was collected byfiltration, washed with diethyl ether and left to air dry to afford thetitle compound as a white solid (40.0 g, 99%). LCMS (Method 3)[M+H]⁺=463.1, R_(T)=2.89 min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.86 (s,1H), 8.78 (dd, 1H), 8.71 (s, 1H), 8.56 (dd, 1H), 8.40 (s, 1H), 7.70 (d,1H), 7.42 (dd, 1H), 7.30 (s, 1H), 6.99 (dd, 1H), 6.47 (t, 1H), 4.86 (s,2H), 1.49 (s, 9H).

Example D

[4-[(2-Amino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-aceticacid

A solution of tert-butyl(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate(1.0 g, 1.92 mmol) in DMF (10 mL) was treated with cesium carbonate(0.69 g, 2.12 mmol) and tert-butyl-bromoacetate (0.43 g, 2.12 mmol) andwas left to stir at room temperature for 2.5 hours. The reaction mixturewas diluted with water and the resultant precipitate was collected byfiltration. The resultant solid was purified by flash chromatography onsilica eluting with 0-70% EtOAc in cyclohexane. Appropriate fractionswere combined and evaporated to afford[4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-aceticacid tert-butyl ester as a white solid (0.91 g, 74%). LCMS (Method 3)[M+H]⁺=633.9, R_(T)=4.46 min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.78 (s,1H), 9.70 (s, 1H), 8.76 (dd, 1H, J=1.8, 6.8 Hz), 8.47 (dd, 1H, J=1.8,4.3 Hz), 8.34 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7Hz), 7.28 (d, 1H, J=8.8 Hz), 6.92 (dd, 1H, J=4.4, 6.9 Hz), 6.47 (t, 1H,J=74.0 Hz), 4.85 (s, 2H), 1.56 (s, 9H), 1.49 (s, 9H).

To a solution of[4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-aceticacid tert-butyl ester (0.91 g, 1.43 mmol) in dichloromethane (7 mL) wasadded TFA (15 mL) and the mixture left to stir at room temperature for 6hours. The solvent was evaporated and the resultant residue azeotropedwith dichlromethane/methanol to afford the title compound as a paleyellow solid (0.66 g, 97%). LCMS (Method 3) [M+H]⁺=477.8, R_(T)=2.95min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 13.15 (br s, 1H), 9.56 (s, 1H),8.93 (dd, 1H, J=1.5, 6.8 Hz), 8.37-8.34 (m, 1H), 8.35 (s, 1H), 7.63 (dd,1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.9 Hz), 7.26(t, 1H, J=73.4 Hz), 7.00 (dd, 1H, J=4.5, 6.8 Hz), 6.58 (br s, 2H), 5.05(s, 2H).

Example E

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide

Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2 mmol) wasadded portionwise to a stirred solution of1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF (100mL) at 0° C. The mixture was then stirred for 10 minutes before additionof diethyl carbonate (7.68 g, 65.0 mmol) and then for an additional 1hour. The mixture was warmed to room temperature for 2 hours and thenheated to 65° C. for 2 hours. Diethyl ether was added, the organicswashed with water and brine, then evaporated to dryness. The resultantresidue was purified by flash chromatography on silica gel (50 to 100%dichloromethane in cyclohexane) to yield 3.41 g of ethyl3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method 1)[M+H]⁺=257.2, R_(T)=3.55 min. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.59 (d,1H), 7.38 (dd, 1H), 6.89 (d, 1H), 4.18 (q, 2H), 3.95 (s, 2H), 3.88 (s,3H), 1.24 (t, 3H).

Bromine (0.70 mL, 13.6 mmol) was added to a solution of ethyl3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (3.39 g, 13.2 mmol) indioxane (25 mL) and stirred for 1 hour. The reaction was poured onto icewater, extracted with ethyl acetate, the organics washed with water andbrine and evaporated to dryness to give ethyl2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method 1)[M+H]⁺=337.2, R_(T)=3.84 min.

A mixture of ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate(assumed to be 13.2 mmol) and thiourea (1.01 g, 13.3 mmol) in ethanol(25 mL) were heated to reflux for 3 hours, then cooled to roomtemperature for 18 hours. The resultant solid was removed by filtrationand the filtrate evaporated under vacuum. DCM was added to the residue,the organics washed with sodium hydrogen carbonate (sat.aq.), water andbrine, and evaporated to dryness. The residue was triturated (DCM) togive ethyl 2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate(1.30 g, 31%) as a yellow solid. LCMS (method 1) [M+H]⁺=313.2,R_(T)=3.15 min. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.77 (s, br, 2H),7.39 (dd, 1H), 7.22 (d, 1H), 7.05 (d, 1H), 4.00 (q, 2H), 3.70 (s, 3H),1.04 (t, 3H).

Copper bromide (1.07 g, 4.79 mmol) in acetonitrile (20 mL) was degassedwith nitrogen and cooled to 0° C. before addition of tert-butyl nitrite(0.80 mL, 6.00 mmol), then a suspension of ethyl2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.25 g, 3.99mmol) in acetonitrile (20 mL) was added and stirred at room temperaturefor 18 hours. The reaction was concentrated under vacuum, ethyl acetateadded, the organics washed with sodium hydrogen carbonate (sat.aq.) andbrine, then evaporated to dryness to give ethyl2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g,93%). LCMS (method 1) [M+H]⁺=378.1, R_(T)=4.26 min. ¹H NMR (400 MHz,DMSO-d₆): δ (ppm) 7.50 (dd, 1H), 7.42 (d, 1H), 7.14 (d, 1H), 4.16 (q,2H), 3.73 (s, 3H), 1.12 (t, 3H).

A mixture of ethyl2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g, 3.72mmol), potassium hydroxide (278 mg) in THF (40 mL) and water (10 mL) wasstirred for 20 hours at ambient temperature. The mixture was treatedwith 1M HCl aq. (ca. 8 mL, 2 eq.), DCM was added, and the organicsseparated and evaporated to dryness to give2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid (1.23 g,95%) as a yellow solid. LCMS (method 2) [M+H]⁺=350.1, R_(T)=3.28 min. ¹HNMR (400 MHz, DMSO-d₆): δ (ppm) 7.47 (dd, 1H), 7.39 (d, 1H), 7.13 (d,1H), 3.73 (s, 3H).

2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid (1.22 g,3.50 mmol), diphenylphosphoryl azide (963 mg, 3.50 mmol) andtriethylamine (354 mg, 3.50 mmol) in tert-butanol (30 mL) were stirredat 85° C. for 4 hours. After cooling, the reaction was partitionedbetween ethyl acetate and water, the organics separated then washed withbrine, and evaporated to dryness. The resulting residues were purifiedby flash chromatography on silica gel (50 to 100% dichloromethane incyclohexane) to yield tert-butyl2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (970 mg, 66%).LCMS (method 1) [M+H-^(t)Bu]⁺=364.8, R_(T)=4.61 min. ¹H NMR (400 MHz,DMSO-d₆): δ (ppm) 7.43 (dd, 1H), 7.30 (d, 1H), 7.11 (d, 1H), 3.77 (s,3H), 1.45 (s, 9H).

TFA (4.0 mL) was added to a solution of tert-butyl2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (360 mg, 0.86mmol) in DCM (10 mL) and water (3 drops). The reaction mixture wasstirred for 1.5 hours at room temperature and then evaporated todryness. The residue was taken up into DCM and washed with sodiumhydrogen carbonate (sat.aq.), water and brine, and concentrated undervacuum to give 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine as anorange residue. LCMS (method 1) [M+H]⁺=321.3, R_(T)=3.63 min. ¹H NMR(400 MHz, DMSO-d₆): δ (ppm) 7.36 (d, 1H), 7.34-7.32 (m, 1H), 7.10 (d,1H), 3.83 (s, 3H).

Using 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine andpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title compound wasprepared following the synthetic procedures described forpyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide with furtherpurification by flash chromatography on silica gel (0 to 40% ethylacetate in DCM) to giveN-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazzolo[1,5-a]pyrimidine-3-carboxamide.LCMS (method 1) [M+H]⁺=465.8, R_(T)=4.01 min. ¹H NMR (400 MHz, DMSO-d₆):δ 10.68 (s, br, 1H), 9.41 (dd, 1H), 8.78 (s, 1H), 8.76 (dd, 1H), 7.57(dd, 1H), 7.50 (d, 1H), 7.37-7.34 (m, 2H), 3.81 (s, 3H).

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-methoxy-phenyl)-thiazol-5-yl]-amide (4.3 g, 9.3mmol) in DCM (90 mL) at −78° C. under an atmosphere of N₂ was addedboron tribromide (1M in DCM, 45 mL, 45 mmol) dropwise. The mixture wasstirred at −78° C. for 1 hour and then allowed slowly to roomtemperature and stirred for a further 16 hours. The mixture was pouredcautiously onto an aqueous solution of sodium hydrogen carbonate,stirred for 15 mins, filtered and the solid collected and dried toafford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide as a beigesolid (6 g, >100%). LCMS (Method 3) [M+H]⁺=450.1, R_(T)=3.71 min. ¹H NMR(400 MHz, DMSO-d₆) δ: 15.96 (s, 1H), 9.18 (dd, 1H, J=1.6, 6.9 Hz), 8.70(dd, 1H, J=1.8, 4.0 Hz), 8.59 (s, 1H), 7.80 (d, 1H, J=2.8 Hz), 7.15 (dd,1H, J=4.0, 7.1 Hz), 7.05 (dd, 1H, J=2.8, 8.6 Hz), 6.77 (d, 1H, J=8.6Hz).

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide (1.1 g, 2.4mmol) in DMF (20 mL) and water (2 mL) was added cesium carbonate (1.1 g,3.4 mmol) and then sodium chlorodifluoroacetate (839 mg, 5.5 mmol). Themixture was stirred at 100° C. for 16 hours before further cesiumcarbonate (2.2 g, 6.8 mmol) and sodium chlorodifluoroacetate (1.7 g, 11mmol) was added and stirring continued at 100° C. for 6 hours. Themixture was allowed to cool to room temperature and partitioned betweenethyl acetate and water and the phases separated. The organic layer waswashed with brine. The combined aqueous layer was extracted with ethylacetate once and the combined organic layer dried (Na₂SO₄), filtered andevaporated. The resultant residue was purified by flash chromatograpy onsilica eluting with 50% ethyl acetate in cyclohexane to give the titlecompound as a yellow solid (710 mg, 59%). LCMS (Method 3) [M+H]⁺=500.1,R_(T)=3.97 min. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.84 (s, 1H), 9.42 (dd,1H, J=1.6, 6.9 Hz), 8.79 (s, 1H), 8.66 (dd, 1H, J=1.6, 4.3 Hz), 7.76 (d,1H, J=2.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.2, 7.0 Hz),7.22 (t, 1H, J=73.1 Hz).

Example 1

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amidehydrochloride

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (200 mg,0.49 mmol) was dissolved in DMF (5 mL),4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester(263 mg, 0.74 mmol) and cesium carbonate (240 mg, 0.74 mmol) were addedand the mixture heated at 90° C. for 2 hours. The mixture was allowed tocool to room temperature, diluted with water and extracted with DCM(×3). The combined organic extract was washed with brine, dried(Na₂SO₄), filtered and evaporated. The resultant yellow oil was purifiedby flash chromatography on silica eluting with 0-2% MeOH in DCM. Theappropriate fractions were collected and evaporated to afford4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylicacid tert-butyl ester a yellow oil. The crude product was taken onto thenext step without further purification. LCMS (Method 4) [M+Na]⁺=610.0;R_(T)=4.30 min.

4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylicacid tert-butyl ester (600 mg, 0.97 mmol) was dissolved in DCM (3 mL)and TFA (3 mL) was added. The mixture was allowed to stir at roomtemperature for 30 minutes. The solvent was evaporated and the residuewas dissolved in MeOH and loaded onto an SCX-2 cartridge which had beenconditioned with MeOH. After flushing with MeOH, the product was elutedwith 2M ammonia in MeOH. Evaporation gave a glass which was purified byHPLC (Method 3). Appropriate fractions were combined and evaporated toafford an off-white solid. The solid was dissolved in MeOH and 1.25Mmethanolic HCl (1 mL) was added. The solvent was evaporated, azeotropedthree times with methanol and triturated with ethyl acetate to affordthe title compound as an off-white solid (144 mg, 28%). LCMS (Method 5)[M+H]⁺=488.0, R_(T)=2.93 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76(s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 8.98 (d, 1H, J=9.9 Hz), 8.69 (dd,1H, J=1.7, 4.3 Hz), 8.67 (s, 1H), 8.38 (s, 1H), 7.65-7.62 (m, 2H), 7.30(dd, 1H, J=4.2, 7.2 Hz), 7.26 (t, 1H, J=73.6 Hz), 4.66-4.57 (m, 1H),3.47-3.42 (m, 2H), 3.17-3.03 (m, 2H), 2.32-2.18 (m, 4H).

Example 2

2-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]-amide

The title compound was prepared from tert-butyl(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate following the procedure outlined in Example 1 to afford anamber solid. LCMS (Method 3) [M+H]⁺=503.3, R_(T)=2.32 min. ¹H NMR (400MHz, DMSO-d₆) δ: (ppm) 9.55 (s, 1H), 8.93 (dd, 1H, J=1.5, 6.8 Hz), 8.37(dd, 1H, J=1.5, 4.5 Hz), 8.29 (s, 1H), 7.64-7.58 (m, 2H), 7.44 (d, 1H,J=8.7 Hz), 7.25 (t, 1H, J=73.5 Hz), 7.00 (dd, 1H, J=4.5, 6.7 Hz), 6.57(s, 2H), 4.33-4.22 (m, 1H), 3.07 (d, 2H, J=12.6 Hz), 2.66-2.57 (m, 2H),2.06-1.96 (m, 2H), 1.89-1.75 (m, 2H).

Example 3

Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

A solution of{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (20.0 g, 43.2 mmol) in DMF (150 mL) was treated with DIPEA (6.7 g,5.2 mmol), cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7mmol) and HATU (18.9 g, 49.7 mmol) and the mixture left to stir at roomtemperature for 1 hour. The reaction mixture was diluted with 0.5Maqueous K₂CO₃ solution and extracted with ethyl acetate (×2). Thecombined organic extract was washed with water (×2) and brine, dried(Na₂SO₄) and evaporated to afford a solid. The resultant solid waspurified by flash chromatography on silica eluting with 0-10% 2MNH₃/MeOH in DCM. Collecting appropriate fractions, followed byevaporation gave the title compound as a cream solid (17.1 g, 69%). LCMS(Method 5) [M+H]⁺=570.9, R_(T)=2.82. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm)9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6 Hz), 8.62-8.63 (m, 2H), 8.27 (s,1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz), 7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H,J=8.8 Hz), 7.25 (dd, 1H, J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07(d, 2H, J=5.9 Hz), 3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2,8.8 Hz), 3.36 (dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz),2.45-2.46 (m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H).

Example 4

Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (3.35 g, 7.25 mmol) was dissolved in DMF (30 mL) and HATU (2.85 g,9.42 mmol) was added. cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (2.0 g, 9.42 mmol) and DIPEA (1.63 mL, 9.42 mmol)were added and the mixture was stirred at room temperature for 17 hours.The volatiles were evaporated and the resultant residue azeotroped withtoluene. The solid was partitioned between water and DCM and the organiclayer was separated, dried (Na₂SO₄) and evaporated. The residue wasdissolved in DCM (10 mL) and TFA (10 mL) was added. The solution wasstirred at room temperature for 4 hours and then evaporated. The residuewas dissolved in MeOH and loaded onto an SCX-2 cartridge which had beenconditioned with MeOH. After flushing with MeOH, the product was elutedwith 2M ammonia in MeOH. The solvent was evaporated and the product wascrystallised from MeOH/Et₂O. The desired product was obtained as anoff-white solid (3.7 g, 90%). LCMS (Method 5) [M+H]⁺=556.9, R_(T)=2.83min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H,J=1.6, 7.0 Hz), 9.38-9.22 (m, 2H), 8.69 (dd, 2H, J=1.7, 4.2 Hz), 8.67(s, 1H), 8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6Hz), 7.47 (d, 1H, J=8.8 Hz), 7.30 (dd, 2H, J=4.3, 7.0 Hz), 7.27 (t, 1H,J=73.4 Hz), 5.15 (s, 2H), 3.80-3.67 (m, 2H), 3.65-3.53 (m, 2H),3.49-3.32 (m, 3H), 3.16-2.94 (m, 4H).

Example 5

Cis pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5ethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amidehydrochloride

To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide(100 mg, 0.18 mmol) in acetonitrile (4 mL) was added potassium carbonate(37 mg, 0.27 mmol) and bromoethane (20 μL, 0.27 mmol). The reaction washeated at 50° C. for 2 hours and then allowed to cool to roomtemperature. The mixture was applied directly to an SCX-2 cartridge.Elution with 2M ammonia in MeOH gave the desired product. The productwas purified by HPLC (Method 1) and the pure fractions were combined aspassed through an SCX-2 cartridge. Elution with 2M ammonia in MeOH gavethe free base on evaporation of the solvent. The solid was dissolved in1.25M methanolic HCl and then the volatiles were evaporated. The HClsalt was crystallised from MeOH/Et₂O and obtained as a white solid (32mg, 40%). LCMS (Method 5) [M+H]⁺=585.0, R_(T)=2.88 min. ¹H NMR (400 MHz,DMSO-d₆) δ: (ppm) 10.44 (d, 1H, J=35.0 Hz), 9.79-9.74 (m, 1H), 9.35 (dd,1H, J=1.3, 7.0 Hz), 8.69 (dd, 1H, J=1.5, 4.2 Hz), 8.67 (s, 1H), 8.31 (d,1H, J=3.8 Hz), 7.64 (dd, 1H, J=2.5, 8.8 Hz), 7.57 (d, 1H, J=2.6 Hz),7.47 (d, 1H, J=8.9 Hz), 7.30 (dd, 1H, J=4.3, 7.0 Hz), 7.27 (t, 1H,J=73.6 Hz), 5.22-5.10 (m, 2H), 3.43 (s, 12H), 3.84-2.77 (m, 12H),1.29-1.19 (m, 3H).

Example 6

Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5-cyclopropylmethylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide(100 mg, 0.18 mmol) in 2,2,2-trifluoroethanol (3 mL) was addedcyclopropanecarbaldehyde (67 μL, 0.90 mmol). After stirring at roomtemperature for 15 minutes, sodium borohydride (21 mg, 0.54 mmol) wasadded and the reaction was heated at 90° C. for 2 hours. MeOH was addedto quench the reaction and the mixture was loaded onto an SCX-2cartridge which had been conditioned with MeOH. After flushing withMeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave acrude product which was purified by HPLC (Method 1). The pure fractionsloaded onto an SCX-2 cartridge which had been conditioned with MeOH.After flushing with MeOH, the product was eluted with 2M ammonia inMeOH. Evaporation gave the title compound as a free base which wascrystallised from MeOH/Et₂O and obtained as a yellow solid (55 mg, 50%).LCMS (Method 5) [M+H]⁺=611.1, R_(T)=3.02 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 10.94-10.88 (m, 1H), 9.57-9.55 (m, 1H), 8.95-8.92 (m, 1H),8.38-8.35 (m, 1H), 8.29-8.28 (m, 1H), 7.65-7.61 (m, 1H), 7.56-7.54 (m,1H), 7.47 (d, 1H, J=8.9 Hz), 7.45-7.07 (m, 1H), 7.08 (d, 1H, J=1.9 Hz),7.02-6.99 (m, 1H), 5.24-5.07 (m, 2H), 3.86-3.52 (m, 5H), 3.52-3.22 (m,2H), 3.17-3.11 (m, 1H), 3.07-3.00 (m, 2H), 3.00-2.79 (m, 1H), 1.27-1.01(m, 1H), 0.63-0.56 (m, 2H), 0.42-0.34 (m, 2H). (Atropisomers present)

Example 7

5-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-((3aR,6aS)-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl)}-amidehydrochloride

A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (500mg, 2.3 mmol) (prepared according to the procedure in Journal ofMedicinal Chemistry, 55(22), 10090-10107; 2012) and5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine(868 mg, 2.3 mmol) were suspended in triethylamine (0.35 mL, 2.5 mmol)and DCM (10 mL) and the mixture was left to stir at room temperature for2 hours. The reaction mixture was diluted with dichloromethane and theresultant organic layer was washed with saturated aqueous sodiumhydrogen carbonate solution, and brine, dried (Na₂SO₄) and evaporated toafford an oil. The resultant oil was purified by flash chromatography onsilica eluting with 0-2% MeOH in DCM. Collecting appropriate fractions,followed by evaporation gave5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amideas a brown oil (1.19 g, 91%).

¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.07 (s, 1H), 8.72 (s, 1H), 8.67 (d,1H, J=7.3 Hz), 8.38 (s, 1H), 7.60 (d, 1H, J=2.3 Hz), 7.51 (dd, 1H,J=2.6, 8.8 Hz), 7.38 (d, 1H, J=8.9 Hz), 6.95 (d, 1H, J=7.2 Hz), 6.43 (t,1H, J=72.8 Hz), 5.41 (d, 1H, J=10.9 Hz), 5.31 (d, 1H, J=11.0 Hz),3.76-3.49 (m, 2H), 1.27 (s, 1H), 0.94-0.84 (m, 2H), 0.00 (s, 9H).

5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide(756 mg, 1.32 mmol) was dissolved in THF (10 mL) and concentratedaqueous ammonia (10 mL) added. The mixture was heated at 50° C. for 3hours then allowed to cool to ambient temperature. The solvent wasevaporated and the residue azeotroped with methanol (×2) to afford5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a white solid (724 mg,99%). LCMS (Method 4) [M+H]⁺=549.9, R_(T)=4.11 min.

A suspension of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide(720 mg, 1.31 mmol) in methanol (20 mL) was treated with concentratedaqueous HCl (3 mL) and the mixture heated at 80° C. for 1 hour. Thesolvent was evaporated and the residue azeotroped with methanol (×3).The resultant solid was triturated with ethyl acetate, collected byfiltration, washed with ethyl acetate and diethyl ether and left to airdry. The residual solid was purified by flash chromatography on silicaeluting with 0-12% 2M NH₃/MeOH in DCM. Collecting appropriate fractions,followed by evaporation gave5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide as a brownsolid (378 mg, 69%). LCMS (Method 4) [M+H]⁺=419.9, R_(T)=2.93

5-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide wasconverted to the title compound following the procedures outlined inExample C and Example 1 to afford a white solid. LCMS (Method 5)[M+H]⁺=586.0, R_(T)=2.58 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76(s, 1H), 9.35 (dd, 1H, J=1.6, 7.1 Hz), 9.38-9.21 (m, 2H), 8.69 (dd, 1H,J=1.7, 4.3 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8Hz), 7.56 (d, 1H, J=2.6 Hz), 7.48 (d, 1H, J=8.6 Hz), 7.30 (dd, 1H,J=4.3, 6.9 Hz), 7.27 (t, 1H, J=73.3 Hz), 5.15 (s, 2H), 3.93-3.67 (m,3H), 3.65-3.32 (m, 6H), 3.19-2.94 (m, 4H).

Example 8

6-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-((3aR,6aS)-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amidehydrochloride

The title compound was prepared from commercially available6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid following theprocedure outlined above for Example B and Example 1 to afford a whitesolid. LCMS (Method 5) [M+H]⁺=585.0, R_(T)=3.03 min. ¹H NMR (400 MHz,DMSO-d₆) δ: (ppm) 10.74-10.49 (m, 1H), 9.70 (s, 1H), 9.21 (dd, 1H,J=1.1, 2.0 Hz), 8.60 (d, 1H, J=2.0 Hz), 8.58 (s, 1H), 8.31 (s, 1H), 7.65(dd, 1H, J=2.7, 8.8 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.49 (d, 1H, J=8.8 Hz),7.28 (t, 1H, J=73.3 Hz), 5.19 (d, 1H, J=16.8 Hz), 5.13 (d, 1H, J=16.8Hz), 3.94-2.88 (m, 10H), 2.82 (s, 3H), 2.39 (s, 3H).

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-{4-[(2-cyano-ethyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-1H-pyrazol-4-yl]-amide

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (32.0 g,79.1 mmol) in DMF (400 mL) was treated with2-chloro-1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-ethanone (20.8 g, 94.9mmol) and Cs₂CO₃ (51.5 g, 158.1 mmol) and the mixture was stirred atroom temperature for 19 hours. The reaction was diluted with water (˜1.6L) and the resultant precipitate was collected by filtration. The solidwas washed with water dried under reduced pressure to affordpyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amideas a beige solid (33.3 g, 72%). LCMS (Method 3) [M+H]⁺=588.2, R_(T)=3.02min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6,6.9 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.8, 4.0 Hz), 8.42 (s, 1H), 7.69(d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.30-7.26 (m, 1H), 7.00(dd, 1H, J=4.2, 6.9 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.06 (s, 2H),4.00-3.95 (m, 4H), 3.74 (dd, 2H, J=5.8, 5.8 Hz), 3.61 (dd, 2H, J=5.8,5.8 Hz), 1.74-1.64 (m, 4H).

A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide(46.7 g, 79.5 mmol) in dioxane (280 mL) was cooled in an ice bath beforebeing treated with concentrated hydrochloric acid (210 mL) at a ratewhich maintained an internal temperature below 22° C. On completeaddition, the reaction was allowed to warm to room temperature andstirred for 4 hours. The reaction was cooled in an ice bath, dilutedwith ethyl acetate and water and the pH of the aqueous phase adjusted to˜8 by the portionwise addition of solid Na₂CO₃. The mixture wasextracted with ethyl acetate (×4) and the combined organic extract wasdried (Na₂CO₃) and evaporated to affordpyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxaneas a beige solid (48.8 g, 97%). LCMS (Method 3) [M+H]⁺=544.2, R_(T)=2.85min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.87 (s, 1H), 8.79 (dd, 1H, J=1.8,7.0 Hz), 8.70 (s, 1H), 8.57 (dd, 1H, J=1.8, 4.0 Hz), 8.47 (s, 1H), 7.67(d, 1H, J=2.8 Hz), 7.43 (dd, 1H, J=2.7, 8.7 Hz), 7.29 (d, 1H, J=8.8 Hz),7.01 (dd, 1H, J=4.3, 7.0 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.14 (s, 2H),3.93 (t, 2H, J=6.2 Hz), 3.85 (t, 2H, J=6.2 Hz), 3.70 (s, 8H), 2.50 (t,2H, J=6.2 Hz), 2.42 (t, 2H, J=6.1 Hz).

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane(36 g, 57.0 mmol) in DCM (500 mL) was treated with 3-amino-propionitrile(5.0 mL, 68.4 mmol) and acetic acid (50 mL). The mixture was cooled inan ice bath before the addition of sodium triacetoxyborohydride (18.1 g,85.4 mmol) portionwise. The reaction was allowed to warm to roomtemperature and stirred for 1.5 hours. The mixture was diluted withmethanol and loaded onto a pad of Isolute® SCX-2 which had beenconditioned with MeOH. After flushing with MeOH, the product was elutedwith 2M ammonia in MeOH. The basic fractions were combined andevaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl)}-1H-pyrazol-4-yl)-amideas a pale brown solid (31.1 g, 91%). LCMS (Method 3) [M+H]⁺=598.2,R_(T)=2.25 min. ¹H NMR (400 MHz, CDCl₃) δ: (ppm) 9.84 (s, 1H), 8.78 (dd,1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.58-8.55 (m, 1H), 8.40 (s, 1H), 7.68(d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H, J=8.7 Hz),7.28 (s, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.50 (t, 1H, J=74.1 Hz),5.08 (d, 1H, J=15.4 Hz), 5.02 (d, 1H, J=15.5 Hz), 4.37 (d, 1H, J=13.4Hz), 3.88 (d, 1H, J=13.4 Hz), 3.22-3.12 (m, 1H), 3.02 (t, 1H, J=6.4 Hz),2.98-2.86 (m, 2H), 2.82-2.72 (m, 1H), 2.52-2.46 (m, 2H), 1.96-1.83 (m,2H), 1.36-1.20 (m, 2H).

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl})-1H-pyrazol-4-yl)-amide(31.1 g, 52.0 mmol) in DCM (500 mL) was treated with 37% aqueousformaldehyde solution (21.3 mL, 286.2 mmol). On complete addition thereaction was cooled in an ice bath before the addition of sodiumtriacetoxyborohydride (44.1 g, 208.2 mmol) portionwise. The reactionmixture was warmed to room temperature and stirred for 1.5 hours, afterwhich, the reaction was filtered and the filtrate diluted with methanol.The mixture was diluted with methanol and loaded onto a pad of Isolute®SCX-2 which had been conditioned with MeOH. After flushing with MeOH,the product was eluted with 2M ammonia in MeOH. The basic fractions werecombined and evaporated. The resultant residue was purified by flashcolumn chromatography on silica eluting with 0-10% 2M NH₃/MeOH in DCM.Appropriate froactions were combined and evaporated. The resultantresidue was recrystallized from ethyl acetate to afford the titlecompound as a pale brown solid (30.7 g, 96%). LCMS (Method 5)[M+H]⁺=612.2, R_(T)=2.84 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75(s, 1H), 9.34 (dd, 1H, J=7.0, 1.6 Hz), 8.70-8.67 (m, 1H), 8.68 (s, 1H),8.32 (s, 1H), 7.63 (dd, 1H, J=8.8, 2.7 Hz), 7.56 (d, 1H, J=2.7 Hz), 7.47(d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=7.0, 4.2 Hz), 7.26 (t, 1H, J=73.4Hz), 5.22-5.24 (m, 2H), 4.38 (d, 1H, J=12.9 Hz), 3.96 (d, 1H, J=13.5Hz), 3.06 (t, 1H, J=12.7 Hz), 2.62-2.65 (m, 6H), 2.22 (s, 3H), 1.72 (d,2H, J=11.9 Hz), 1.34-1.40 (m, 2H).

Example 142

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[1-[1-(3-acetylaminopropyl)piperidin-4-yl]-3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amidehydrochloride

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amide(100 mg, 0.20 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (71mg, 0.3 mmol) and potassium carbonate (45 mg, 0.32 mmol) in DMF (2 mL)was heated at 60° C. for 1.5 hours. The reaction mixture was allowed tocool to ambient temperature, diluted with water and extracted withdichloromethane. The organic layer was separated, washed with brine,dried (Na₂SO₄) and evaporated. The resultant residue was chromatographedon silica eluting with dichloromethane on a gradient of 2M ammonia inmethanol (0-6%) to give[3-(4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamicacid tert-butyl ester as a yellow oil (131 mg, 100%). LCMS (Method 4)[M+H]⁺=675.0, R_(T)=2.86 min.

[3-(4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamicacid tert-butyl ester (129 mg, 0.20 mmol) was dissolved in DCM (2 mL)and TFA (2 mL) was added. The reaction was stirred at room temperaturefor 1 hour and then evaporated to dryness. The residue was dissolved inMeOH and loaded onto an SCX-2 cartridge which had been conditioned withMeOH. After flushing with MeOH, the product was eluted with 2M ammoniain MeOH. Evaporation of the basic fractions gave a residue which wasdissolved in pyridine (2 mL). Acetyl chloride (21 μL, 0.30 mmol) wasadded and the solution was allowed to stand at room temperature for 5days. The volatiles were evaporated and azeotroped with toluene. Theresidue was dissolved in MeOH and loaded onto an SCX-2 cartridge whichhad been conditioned with MeOH. After flushing with MeOH, the productwas eluted with 2M ammonia in MeOH. Evaporation gave a glassy solidwhich was purified by HPLC (Method 3). The pure amine was dissolved inMeOH and 1.25M methanolic HCl was added. The volatiles were evaporatedand the solid product was triturated with EtOAc/Et₂O to give the titlecompound as a white solid (40 mg, 32%). LCMS (Method 5) [M+H]⁺=587.0,R_(T)=2.91 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.89 (s, 1H), 9.76(s, 1H), 9.35 (dd, 1H, J=1.5, 7.0 Hz), 8.69 (dd, 1H, J=1.6, 4.2 Hz),8.67 (s, 1H), 8.39 (s, 1H), 8.04 (t, 1H, J=5.8 Hz), 7.67-7.61 (m, 2H),7.46 (d, 2H, J=8.4 Hz), 7.31 (dd, 1H, J=4.2, 6.9 Hz), 7.26 (t, 1H,J=73.4 Hz), 4.64-4.54 (m, 1H), 3.64 (d, 2H, J=12.2 Hz), 3.21-3.01 (m,6H), 2.40-2.29 (m, 4H), 1.84 (m, 5H).

Example 302

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-1H-pyrazol-4-yl}-amidehydrochloride

A solution of 4-iodo-benzoyl chloride (4.72 g, 17.71 mmol) in DCM (70mL) at 0° C. was treated with dimethyl-piperidin-4-yl-amine (2.27 g,17.71 mmol). The resultant suspension was warmed to room temperature andstirred for 2.5 hours. The reaction mixture was diluted with 1M aqueousNa₂CO₃ solution and the phases separated. The aqueous phase wasextracted twice with DCM and the combined organic phase was dried(Na₂SO₄) and evaporated to afford(4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone as a whitesolid (6.2 g, 98%). LCMS (Method 3) [M+H]⁺=359.2, R_(T)=1.82 min.

A microwave vial was charged with pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (100mg, 0.25 mmol),(4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone (107 mg, 0.30mmol), copper (I) iodide (15 mg, 0.08 mmol), potassium carbonate (73 mg,0.53 mmol), trans-N,N′-dimethyl-1,2-cyclohexane diamine (24 μL, 0.15mmol). The vessel was sealed and purged with argon before the additionof toluene (1.0 mL). The reaction mixture was stirred at 110° C. for 18hours. The reaction was cooled to room temperature, diluted with waterand the resultant precipitate was collected by filtration, washed withethyl acetate and dried under reduced pressure. The resultanat solid waspurified by MDAP (Method 1), the solid was taken up into a mixture ofMeOH/DCM and loaded onto an Isolute®SCX-2 cartridge which had beenconditioned with MeOH. The cartridge was washed with MeOH then elutedwith 2M NH₃/MeOH. The basic fractions were combined, evaporated and theresultant solid suspended in MeOH before being treated with 1.25M HCl inMeOH. The suspension was allowed to evaporate and the solid wastriturated with ethyl acetate, dried under reduced pressure giving thetitle compound as a yellow solid (67 mg, 40%). LCMS (Method 5)[M+H]⁺=635.2, R_(T)=3.27 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.88(s, 1H), 9.38 (dd, 1H, J=7.1, 1.8 Hz), 9.04 (s, 1H), 8.71 (s, 1H), 8.70(dd, 1H, J=4.3, 1.7 Hz), 8.04-7.99 (m, 2H), 7.79 (d, 1H, J=2.7 Hz), 7.72(dd, 1H, J=8.8, 2.6 Hz), 7.63-7.57 (m, 2H), 7.53 (d, 1H, J=8.8 Hz), 7.33(dd, 1H, J=7.0, 4.3 Hz), 7.31 (t, 1H, J=73.1 Hz), 4.65 (brs, 1H), 2.98(s, 2H), 2.67 (s, 6H), 2.14-1.82 (m, 2H), 1.69-1.54 (m, 2H).

Example 188

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethylamino-piperidin-1-yl)-thiazol-5-yl]-amide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (100mg, 0.2 mmol) and 4-dimethylaminopiperidine (128 mg, 1 mmol) weredissolved in DMA (1 ml) and heated in a microwave at 160° C. for 1 hour.The residue was dissolved in MeOH and loaded onto an SCX-2 cartridgewhich had been conditioned with MeOH. After flushing with MeOH, theproduct was eluted with 2M ammonia in MeOH. The resulting yellow glasswas purified by MDAP (Method 1). Appropriate fractions were combined andevaporated to afford a yellow solid. The residue was dissolved in MeOHand loaded onto an SCX-2 cartridge which had been conditioned with MeOH.After flushing with MeOH, the product was eluted with 2M ammonia in MeOHto give the title compound as a yellow-orange solid (43 mg, 39%). LCMS(Method 5) [M+H]⁺=548.1, R_(T)=3.20 min. ¹H NMR (400 MHz, DMSO-d₆) δ:(ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.63(dd, 1H, J=1.6, 4.2 Hz), 7.66 (d, 1H, J=2.7 Hz), 7.59 (dd, 1H, J=2.6,8.8 Hz), 7.41 (d, 1H, J=9.0 Hz), 7.31 (dd, 1H, J=4.2, 6.7 Hz), 7.18 (t,1H, J=73.5 Hz), 3.93 (d, 2H, J=12.7 Hz), 3.02 (dd, 2H, J=10.3, 12.3 Hz),3.05-2.95 (m, 1H), 2.40-2.26 (m, 6H), 1.92-1.89 (m, 2H), 1.58-1.47 (m,2H).

Example 189

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(4-(5-chloro-2-difluoromethoxy-phenyl)-2-{4-[(2-cyano-ethyl)-methyl-amino]-piperidin-1-yl}-thiazol-5-yl)-amide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (820mg, 1.64 mmol) and 1,4 dioxa-8-azaspiro[4.5]decane (1.05 ml, 8.2 mmol)were dissolved in DMA (10 ml) and heated in a microwave at 165° C. for 1hour. The reaction mixture partitioned between ethyl acetate and waterand the phases separated. The organic layer was washed with brine. Thecombined aqueous layers were extracted with ethyl acetate once and theorganic layers combined, dried (Na₂SO₄), filtered and the solventremoved. The crude product was chromatographed on silica eluting with50-60% ethyl acetate in cyclohexane. Appropriate fractions were combinedand evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-thiazol-5-yl]-amideas a yellow solid (541 mg, 59%). LCMS (Method 3) [M+H]⁺=563.3,R_(T)=3.68 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.26 (s, 1H), 9.37(dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.64 (dd, 1H, J=1.5, 4.4 Hz),7.68 (d, 1H, J=2.5 Hz), 7.59 (dd, 1H, J=2.7, 8.7 Hz), 7.42 (d, 1H, J=8.5Hz), 7.31 (dd, 1H, J=4.3, 7.0 Hz), 7.18 (t, 1H, J=73.8 Hz), 3.94 (s,4H), 3.52 (dd, 4H, J=5.7, 5.7 Hz), 1.75 (dd, 4H, J=5.7, 5.7 Hz).

[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-thiazol-5-yl]-amide(536 mg, 0.95 mmol) was dissolved in dioxane (10 ml) and conc.hydrochloric acid (10 ml) and stirred at room temperature for 3 hours.The mixture was cooled to 0° C. and basified to ca. pH 13 with 50%aqueous sodium hydroxide and then partitioned between ethyl acetate andwater and the phases separated. The organic layer was washed with brine.The combined aqueous layers were extracted with ethyl acetate once andthe organic layers combined, dried (Na₂SO₄), filtered and the solventremoved to yield pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-yl]-amideas a yellow-orange solid (465 mg, 94%). LCMS (Method 3) [M+H]⁺=519.3,R_(T)=3.39 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.30 (s, 1H), 9.38(dd, 1H, J=1.5, 7.1 Hz), 8.70 (s, 1H), 8.65 (dd, 1H, J=1.4, 4.3 Hz),7.70 (d, 1H, J=2.5 Hz), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.43 (d, 1H, J=9.2Hz), 7.32 (dd, 1H, J=4.2, 7.1 Hz), 7.20 (t, 1H, J=74.0 Hz), 3.81 (dd,4H, J=6.2, 6.2 Hz), 2.54 (d, 4H, J=6.1 Hz).

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-yl]-amide(90 mg, 0.17 mmol) was dissolved in DCM (2 ml) andN-methyl-P3-alaninenitrile (20 μl, 0.21 mmol), acetic acid (200 μl) andmacroporous polymer supported cyanoborohydride (166 mg, 0.36 mmol) weresuccessively added and stirred at room temperature for 16 hours. Themixture was diluted with MeOH and loaded onto an SCX-2 cartridge whichhad been conditioned with MeOH. After flushing with MeOH, the productwas eluted with 2M ammonia in MeOH. The resulting yellow glass waspurified by MDAP (Method 1). Appropriate fractions were combined andevaporated to afford a yellow glass. The residue was dissolved in MeOHand loaded onto an SCX-2 cartridge which had been conditioned with MeOH.After flushing with MeOH, the product was eluted with 2M ammonia in MeOHto give the title compound as a yellow solid (46 mg, 46%). LCMS (Method5) [M+H]⁺=587.2, R_(T)=3.19 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm)10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.64 (dd, 1H,J=1.6, 4.3 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.59 (dd, 1H, J=2.7, 8.9 Hz),7.41 (d, 1H, J=8.6 Hz), 7.31 (dd, 1H, J=4.3, 7.1 Hz), 7.18 (t, 1H,J=73.9 Hz), 3.94 (d, 2H, J=12.8 Hz), 3.04-2.96 (m, 2H), 2.72-2.60 (m,5H), 2.24 (s, 3H), 1.79 (d, 2H, J=10.9 Hz), 1.59-1.47 (m, 2H).

Example 205

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-thiazol-5-yl]-amide

The title compound was prepared in an analogous manner topyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethylamino-piperidin-1-yl)-thiazol-5-yl]-amideto afford the title compound as a yellow-orange solid. LCMS (Method 5)[M+H]⁺=520.2, R_(T)=3.02 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.25(s, 1H), 9.37 (dd, 1H, J=1.6, 7.0 Hz), 8.69 (s, 1H), 8.64 (dd, 1H,J=1.6, 4.3 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.59 (dd, 1H, J=2.7, 8.8 Hz),7.42 (d, 1H, J=9.2 Hz), 7.31 (dd, 1H, J=4.2, 7.3 Hz), 7.18 (t, 1H,J=73.7 Hz), 3.41 (dd, 4H, J=4.9, 4.9 Hz), 2.48-2.42 (m, 4H), 2.24 (s,3H).

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-dimethylamino-prop-1-ynyl)-thiazol-5-yl]-amide

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (150mg, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (11 mg,0.015 mmol), copper(I)iodide (5 mg, 0.024 mmol) in THF (1 mL) was addedpropargyl alcohol (35 pL, 0.6 mmol) then triethylamine (1 mL) under anatmosphere of nitrogen. The resultant mixture was stirred at 50° C. for3 hours before being cooled to room temperature. The mixture waspartitioned between ethyl acetate and water. The phases were separatedand the organic phase washed with brine, dried (Na₂SO₄) and evaporated.The resultant residue was purified by flash column chromatography onsilica eluting with 80% ethyl acetate in cyclohexane to affordpyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol-5-yl]-amideas a yellow solid (112 mg, 78%). LCMS (Method 3) [M+H]⁺=476.2,R_(T)=3.19 min.

To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol-5-yl]-amide(110 mg, 0.23 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in DCM (3mL) was added carbon tetrabromide (132 mg, 0.4 mmol) portionwise. Thereaction was stirred at room temperature before the addition of 2Mmethylamine in THF (1 mL). The resultant mixture was stirred at roomtemperature for 3 hours. The mixture was evaporated and the residuetaken up into MeOH and loaded onto an Isolute® SCX-2 cartridge which hadbeen conditioned with MeOH. The cartridge was washed with MeOH beforebeing eluted with 2M NH₃ in MeOH. The basic fractions were combined andevaporated. The residue was purified by MDAP (Method 1), afterevaporation the material was taken up into MeCN and loaded onto anIsolute® SCX-2 cartridge which had been conditioned with MeCN. Thecartridge was washed with MeCN before being eluted with 2M NH₃ in MeOH.The basic fractions were combined and evaporated, giving the titlecompound as an orange solid (18 mg, 15%). LCMS (Method 5) [M+H]⁺=503.0,R_(T)=3.16 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.85 (s, 1H), 9.41(dd, 1H, J=7.1, 1.3 Hz), 8.79 (s, 1H), 8.63 (dd, 1H, J=4.4, 1.5 Hz),7.76 (d, 1H, J=2.6 Hz), 7.72 (dd, 1H, J=8.8, 2.6 Hz), 7.52 (d, 1H, J=8.8Hz), 7.36 (dd, 1H, J=7.0, 4.3 Hz), 7.19 (t, 1H, J=73.2 Hz), 3.61 (s,2H), 2.29 (s, 6H).

Example 211

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diazaspiro[3.4]oct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amidewas prepared using a method similar to that used in the synthesis ofpyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-ylamide. LCMS (Method 5) [M+H]⁺=556.9, R_(T)=2.84 min.

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diaza-spiro[3.4]oct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide(70 mg, 0.13 mmol) and paraformaldehyde (19 mg, 0.63 mmol) were stirredin 2,2,2-trifluoroethanol for 15 minutes. Sodium borohydride (14 mg,0.38 mmol) was added and the reaction mixture was heated at 90° C. for 2hours. The reaction mixture was allowed to cool to room temperature andwas quenched with MeOH. The mixture was loaded onto an SCX-2 cartridgewhich had been conditioned with MeOH. After flushing with MeOH, theproduct was eluted with 2M ammonia in MeOH. Evaporation gave a crudeproduct which was was purified by HPLC (Method 1). The pure fractionswere loaded onto an SCX-2 cartridge which had been conditioned withMeOH. After flushing with MeOH, the product was eluted with 2M ammoniain MeOH. Evaporation gave the free base which was crystallised fromMeOH/Et₂O. The title compound was obtained as a white solid (28 mg,39%). LCMS (Method 5) [M+H]⁺=570.9, R_(T)=2.86 min. ¹H NMR (400 MHz,DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.0 Hz), 8.69-8.66(m, 2H), 8.34 (s, 1H), 8.15 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.9 Hz), 7.57(d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 2H, J=4.3, 7.1 Hz),7.25 (t, 1H, J=73.5 Hz), 4.94 (s, 2H), 4.04 (q, 2H, J=8.8 Hz), 3.90-3.81(m, 2H), 2.69 (s, 2H), 2.27 (s, 3H), 2.03 (dd, 2H, J=6.8, 6.8 Hz).

Example 227

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

The title compound was prepared in an analogous manner tocis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amideusing{3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid and methyl piperazine to afford the title compound as a pale yellowsolid. LCMS (Method 5) [M+H]⁺=545.1, R_(T)=2.89 min. ¹H NMR (400 MHz,CDCl₃) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 7.0 Hz), 8.71 (s,1H), 8.56 (dd, 1H, J=1.7, 4.1 Hz), 8.41 (s, 1H), 7.69 (d, 1H, J=2.6 Hz),7.41 (dd, 1H, J=2.6, 8.7 Hz), 7.28 (d, 1H, J=9.1 Hz), 7.00 (dd, 1H,J=4.2, 7.0 Hz), 6.47 (t, 1H, J=74.1 Hz), 5.04 (s, 2H), 3.72-3.65 (m,2H), 3.57 (dd, 2H, J=4.8, 4.8 Hz), 2.47-2.39 (m, 4H), 2.31 (s, 3H).

Example 233

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide

The title compound was prepared in an analogous manner tocis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amideusing{3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid and ethyl piperazine to afford the title compound as a white solid.LCMS (Method 5) [M+H]⁺=559.1, R_(T)=2.89 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.0 Hz), 8.69-8.67 (m, 2H),8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz), 7.46(d, 1H, J=9.0 Hz), 7.29 (dd, 1H, J=4.2, 7.1 Hz), 7.25 (t, 1H, J=73.5Hz), 5.23 (s, 2H), 3.50-3.49 (m, 4H), 2.41-2.32 (m, 6H), 1.02 (t, 3H,J=7.1 Hz).

Example 253

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid{4-(5-chloro-2-difluoromethoxy-phenyl)-2-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-thiazol-5-yl}-amidehydrochloride

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (100mg, 0.2 mmol), 4-carboxybenzeneboronic acid (40 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex(16 mg, 0.02 mmol) and potassium carbonate (110 mg, 0.8 mmol) weredissolved in dioxane (3.2 ml) and water (0.8 ml) under an atmosphere ofN₂ and heated in a microwave at 120° C. for 30 mins. The mixture waspartitioned between ethyl acetate and water and the phases separated.The aqueous layer was acidified with 1M HCl and the resultingprecipitate was filtered and the solid collected and dried.

The resultant residue was dissolved in DMF (2 ml) and DIPEA (52 μl, 0.3mmol) and HATU (91 mg, 0.24 mmol) were added and stirred at roomtemperature for 5 mins before the addition of 4-dimethylaminopiperidine(31 mg, 0.24 mmol). The resulting mixture was stirred at roomtemperature for a further 16 hours. The mixture was diluted with MeOHand loaded onto an SCX-2 cartridge which had been conditioned with MeOH.After flushing with MeOH, the product was eluted with 2M ammonia inMeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1).Appropriate fractions were combined and evaporated to afford anoff-white solid. The residue was dissolved in MeOH and loaded onto anSCX-2 cartridge which had been conditioned with MeOH. After flushingwith MeOH, the product was eluted with 2M ammonia in MeOH to give thetitle compound as an off-white solid (27 mg, 21%). LCMS (Method 5)[M+H]⁺=652.3, R_(T)=3.35 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.82(1H, s), 9.42 (1H, dd, J=1.4, 6.9 Hz), 8.80 (1H, s), 8.65 (1H, dd,J=1.4, 4.3 Hz), 8.03 (2H, d, J=8.2 Hz), 7.85 (1H, d, J=2.6 Hz), 7.73(1H, dd, J=2.7, 8.8 Hz), 7.56-7.51 (3H, m), 7.37 (1H, dd, J=4.3, 6.9Hz), 7.25 (1H, t, J=73.5 Hz), 4.71-4.39 (m, 1H), 3.73-3.65 (1H, m),3.52-3.41 (1H, m), 3.13-3.11 (1H, m), 2.89-2.88 (1H, m), 2.51 (s, 6H),2.06-1.74 (2H, m), 1.49 (2H, dd, J=7.6, 14.7 Hz).

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethylamino-piperidin-1-ylmethyl)-thiazol-5-yl]-amide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (600mg, 1.2 mmol), potassium vinyltrifluoroborate (177 mg, 1.32 mmol),[1,1′-bi s(diphenylphosphino)ferrocene]dichloropalladium dichloromethanecomplex (48 mg, 0.06 mmol) and DIPEA (627 μl, 3.6 mmol) were dissolvedin 2-propanol (9 ml) and water (4.5 ml) under an atmosphere on N₂ andheated in a microwave at 100° C. for 40 mins. The mixture waspartitioned between ethyl acetate and water and the phases separated.The organic layer was washed with brine, dried (Na₂SO₄), filtered andthe solvent removed.

The resulting residue was suspended in acetone (12 ml) and water (1.2ml), then potassium osmate dihydrate (25 mg, 0.06 mmol) andN-methylmorpholine N-oxide (280 mg, 2.4 mmol) were added and the mixturestirred vigorously at room temperature for 16 hours. The reaction wasquenched by the addition of solid sodium metabisulfite (2 g), and thenpartitioned between ethyl acetate and water and the phases separated.The organic layer was washed with brine. The combined aqueous layerswere extracted with ethyl acetate once and the organic layers combined,dried (Na₂SO₄), filtered and the solvent removed.

The resulting residue was dissolved in THF (15 ml) and water (15 ml) andsodium periodate (514 mg, 2.4 mmol) was added and the mixture wasstirred vigorously at room temperature for 1.5 hours. The reactionmixture partitioned between ethyl acetate and water and the phasesseparated. The organic layer was washed with brine. The combined aqueouslayer was extracted with ethyl acetate once and the organic layercombined, dried (Na₂SO₄), filtered and the solvent removed to yield thetitle compound as an orange solid (509 mg, 94%).

A portion of the resultant solid (100 mg, 0.22 mmol) was dissolved inDCM (2 ml) and 4-dimethylaminopiperidine (33 mg, 0.26 mmol), acetic acid(200 μl) and macroporous polymer supported cyanoborohydride (216 mg,0.44 mmol) were successively added and stirred at room temperature for16 hours. The mixture was diluted with MeOH and loaded onto an SCX-2cartridge which had been conditioned with MeOH. After flushing withMeOH, the product was eluted with 2M ammonia in MeOH.

The resulting yellow glass was purified by HPLC (MDAP, Method 1).Appropriate fractions were combined and evaporated to afford a yellowglass. The residue was dissolved in MeOH and loaded onto an SCX-2cartridge which had been conditioned with MeOH. After flushing withMeOH, the product was eluted with 2M ammonia in MeOH to give the titlecompound as a pale yellow solid (52 mg, 42%). LCMS (Method 5)[M+H]⁺=562.1, R_(T)=2.56 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.59(s, 1H), 9.39 (dd, 1H, J=1.6, 7.0 Hz), 8.75 (s, 1H), 8.62 (dd, 1H,J=1.6, 4.3 Hz), 7.48 (d, 1H, J=8.8 Hz), 7.34 (dd, 1H, J=4.2, 7.0 Hz),7.17 (t, 1H, J=73.4 Hz), 3.78 (s, 2H), 2.98 (d, 2H, J=11.5 Hz), 2.19 (s,6H), 2.17-2.08 (m, 3H), 1.79-1.72 (m, 2H), 1.50-1.38 (m, 2H).

Example 264

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-thiazol-5-yl]-amide

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (200mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70 mg, 0.56mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol), tri-tert-butylphosphine hydrofluoroborate (3.5 mg, 0.011 mmol), molybdenumhexacarbonyl (53 mg, 0.2 mmol) and DBU (40 μl, 0.27 mmol) were dissolvedin THF (2 ml) and heated in a microwave at 125° C. for 15 mins. Theresidue was dissolved in MeOH and loaded onto an SCX-2 cartridge whichhad been conditioned with MeOH.

After flushing with MeOH, the product was eluted with 2M ammonia inMeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1).Appropriate fractions were combined and evaporated to afford a yellowsolid. The residue was dissolved in MeOH and loaded onto an SCX-2cartridge which had been conditioned with MeOH. After flushing withMeOH, the product was eluted with 2M ammonia in MeOH to give the titlecompound as a pale yellow solid (18 mg, 8%). LCMS (Method 5)[M+H]⁺=574.1, R_(T)=3.06 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 10.88(s, 1H), 9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H,J=1.5, 4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz),7.54 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H,J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9, 12.3Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H), 3.02-2.92 (m,1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s, 3H).

Example 297

2-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[1-(3-amino-cyclobutyl)-3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared in an analogous manner to2-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[3-(5-chloro-2-difluoromethoxy-phenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]-amideusing tert-butyl(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate and trans-toluene-4-sulfonic acid3-tert-butoxycarbonylamino-cyclobutyl ester to afford the title compoundas a white solid. LCMS (Method 5) [M+H]⁺=489.1, R_(T)=2.87 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.53 (s, 1H), 8.93 (dd, 1H, J=1.6, 6.8 Hz),8.37-8.34 (m, 2H), 7.63-7.60 (m, 2H), 7.45 (d, 1H, J=7.2 Hz), 7.25 (t,1H, J=72.6 Hz), 7.00 (dd, 1H, J=4.5, 6.5 Hz), 6.56 (s, 2H), 4.51-4.41(m, 1H), 3.18-3.07 (m, 1H), 2.75-2.67 (m, 2H), 2.24-2.14 (m, 2H).

Example 304

N-[1-(2-carbamimidoylethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(500 mg, 1.24 mmol), 3-bromopropanenitrile (412 mg, 3.08 mmol), Cs₂CO₃(1.21 g, 3.70 mol) in N,N-dimethylformamide (15 mL) was purged with agentle flow of nitrogen gas. The resulting mixture was stirred in asealed tube at 65° C. for 16 then poured into water (200 mL). The crudeproduct was collected by filtration and then purified by flashchromatography on silica eluting with ethyl acetate/petroleum ether(1:2). Appropriate fractions were collected and evaporated to affordN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid (320 mg, 57%). LCMS (Method 17) [M+H]⁺=458.1,R_(T)=1.67 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.44 mmol) and methanol (280 mg, 8.74 mmol) in toluene (10 mL)was added acetyl chloride (341 mg, 4.34 mmol) dropwise with stirring at0° C. The resulting solution was stirred for 2 hours at roomtemperature. To this was added a solution of concentrated ammoniumhydroxide (459 mg) in methanol (3 mL) dropwise with stirring at 0° C.The resulting solution was stirred overnight at room temperature andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica eluting with dichloromethane/methanol (5/1).Appropriate fractions were collected and concentrated to afford a whitesolid (130 mg), which was further purified by high pH Prep-HPLC toaffordN-[1-(2-carbamimidoylethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid (36.8 mg). LCMS (Method 17) [M+H]+=475.1 (Note: undermethod 17, decomposition products observed), LCMS (method 18) R_(T)=6.52min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.72 (s, 1H), 9.36 (dd, J=1.8,7.2 Hz, 1H), 8.68-8.66 (m, 2H), 8.35 (s, 1H), 7.64-7.60 (m, 2H),7.48-7.24 (m, 3H), 6.39 (s, 2H), 4.44 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.2Hz, 2H).

Example 306

Ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate

A mixture ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(3.00 g, 7.41 mmol), Cs₂CO₃ (9.90 g, 30.38 mmol), tetrahydrofuran (90mL), 1,2-dibromoethane (7.00 g, 37.26 mmol) was stirred at 70° C. for 3hours in an oil bath. The mixture was allowed to cool to ambienttemperature then concentrated under reduced pressure. The residue waspurified by flash chromatography on silica eluting with ethylacetate/petroleum ether (1:1) to affordN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamideas a off-white solid (2.2 g, 58%). TLC: R_(f)=0.6; ethylacetate/petroleum ether=1:1; LCMS (Method 14) [M+H]+=513.2, R_(T)=1.03min.

A mixture ofN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.39 mmol), triethylamine (394 mg, 3.89 mmol), ethyl2-aminoacetate hydrochloride (271 mg, 1.94 mmol) in ethanol (20 mL) wasstirred at 80° C. for 24 hours then concentrated under reduced pressure.The crude product was purified by high pH Prep-HPLC to afford the titlecompound as an off-white solid (31.9 mg, 15%). LCMS (Method 14)[M+H]⁺=534.2, R_(T)=1.13 min. H NMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.11(dd, J=1.5, 7.0 Hz, 1H), 8.66-6.65 (m, 2H), 8.36 (s, 1H), 7.68 (d, J=2.4Hz, 1H), 7.58 (dd, J=2.7, 8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.39 (dd,J=4.5, 7.2 Hz, 1H), 6.55 (t, J=73.5 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H),4.17 (q, J=7.2 Hz, 2H), 3.41 (s, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.25 (t,J=7.2 Hz, 3H).

Example 310

2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]aceticacid

Potassium hydroxide (200 mg, 3.56 mmol) in water (2 mL) was added to asolution of ethyl2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate(200 mg, 0.32 mmol) in ethanol (20 mL), The resulting solution wasstirred at room temperature for 2 h and neutralized with 1 M HCl aqueoussolution until pH˜7. The resultant solution was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (30.0% upto 60.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 20.6 mg (11%)of2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]aceticacid as a white solid. LCMS (Method 26) [M+H]⁺=589.2, R_(T)=0.82 min. ¹HNMR (400 MHz, CD₃OD-d₄) δ: (ppm) 9.10 (dd, 1H, J=1.6, 7.2 Hz), 8.66 (s,1H), 8.65 (d, 1H, J=2.8 Hz), 8.38 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 7.57(dd, 1H, J=2.4, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (J=4.0, 6.8 Hz),6.63 (t, 1H, J=73.6 Hz), 5.30 (s, 2H), 3.93-3.86 (m, 4H), 3.50 (s, 2H),3.32-3.13 (m, 4H).

Example 311

2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]aceticacid

A mixture of t-butyl N-(piperidin-4-yl)carbamate (627 mg, 3.13 mmol) andN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide(400 mg, 0.78 mmol) in DMF (5 mL) was stirred at 100° C. for 5 h andcooled to room temperature. Water (50 mL) was added. The precipitateswere collected by filtration and dried. This resulted in 400 mg (81%) oftert-butylN-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]carbamateas a yellow solid. LCMS (Method 21) [M+H]+=631.1, R_(T)=1.21 min.

Saturated HCl dioxane solution (15 mL) was added to tert-butylN-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]carbamate(400 mg, 0.63 mmol). The resulting solution was stirred at roomtemperature overnight and concentrated under vacuum. The pH value of theremaining solution was adjusted to 8-9 with saturated aqueous Na₂CO₃.The resulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica eluting with MeOH/DCM (1:1)to afford 330 mg (98%) ofN-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LCMS (Method 28) [M+H]⁺=531.1, R_(T)=0.49 min.

Potassium carbonate (98 mg, 0.71 mmol) was added to a solution ofN-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(290 mg, 0.55 mmol) and tert-butyl 2-bromoacetate (96 mg, 0.49 mmol) inDMF (5 mL). The resulting mixture was stirred at 50° C. overnight. Theresulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica eluting with 15% MeOH in DCMto afford 150 mg (43%) of tert-butyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]-acetateas a yellow solid. LCMS (Method 24) [M+H]⁺=645.2, R_(T)=1.39 min.

A solution of tert-butyl ester from previous step (150 mg, 0.23 mmol) inDCM (2 mL) and TFA (2 mL) was stirred at room temperature overnight. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% FA and MeCN (20.0% up to 27.0% in 10 min, up to 95.0%in 1 min, hold 95.0% in 1 min, down to 20.0% in 2 min); Detector, UV254/220 nm. This resulted in 63.5 mg (43%) of the formic acid salt of2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]aceticacid as an off-white solid. LCMS (Method 25) [M+H]⁺=589.1, R_(T)=0.85min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.34 (d, 1H, J=8.0Hz), 8.79-8.65 (m, 2H), 8.46-8.35 (m, 1H), 7.64-6.98 (m, 5H), 4.30 (s,2H), 3.10-2.82 (m, 5H), 2.54-2.53 (m, 2H), 2.17-1.93 (m, 4H), 1.58-1.45(m, 2H).

Example 312

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

2-(Methylsulfanyl)ethan-1-amine (0.5 mL, 5.34 mmol) was added to asolution ofN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(120 mg, 0.23 mmol) in CH₃CN (3 mL). The resulting solution was stirredat 80° C. for 2 h and concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 10 mmol NH₄HCO₃ and MeCN (40.0% up to 57.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector,UV 254/220 nm. This resulted in 58.2 mg (48%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]-amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LCMS (Method 20) [M+H]⁺=522.2, R_(T)=2.50 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz),8.67 (dd, 1H, J=1.6, 4.4 Hz), 8.67 (s, 1H), 8.36 (s, 1H), 7.68-7.61 (m,2H), 7.46-7.44 (m, 1H), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.06 (t, 1H,J=73.2 Hz), 4.23 (t, 2H, J=6.4 Hz), 2.98 (t, 2H, J=6.0 Hz), 2.71 (t, 2H,J=6.8 Hz), 2.53 (t, 2H, J=6.8 Hz), 2.03 (s, 3H).

N-[1-[2-(benzylamino)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analogous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared fromN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideand phenylmethanamine. LCMS (Method 20) [M+H]⁺=538.2, R_(T)=2.70 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.84 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8Hz), 8.67 (dd, 1H, J=1.6, 4.4 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.64-7.59(m, 2H), 7.46-7.42 (m, 1H), 7.32-7.19 (m, 6H), 7.06 (t, 1H, J=73.2 Hz),4.25 (t, 2H, J=6.4 Hz), 3.73 (s, 2H), 2.93 (t, 2H, J=6.4 Hz).

Example 314

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-2-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analogous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared fromN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideand pyridin-2-ylmethanamine. LCMS (Method 20) [M+H]⁺=539.2, R_(T)=2.53min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H,J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.0 Hz), 8.67 (s, 1H), 8.49 (d, 1H,J=4.0 Hz), 8.37 (s, 1H), 7.72 (dd, 1H, J=1.6, 7.6 Hz), 7.70-7.61 (m,2H), 7.46-7.06 (m, 5H), 4.27 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 2.98 (t,2H, J=6.0 Hz).

Example 315

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-4-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analogous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared fromN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideand pyridin-4-ylmethanamine. LCMS (Method 25) [M+H]⁺=539.1, R_(T)=1.45min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H,J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.4 Hz), 8.45 (d, 2H, J=6.0 Hz),8.38 (s, 1H), 7.64-7.59 (m, 2H), 7.44 (d, 1H, J=8.8 Hz), 7.32-7.28 (m,3H), 7.07 (t, 1H, J=73.2 Hz), 4.26 (t, 2H, J=6.0 Hz), 3.76 (s, 2H), 2.93(t, 2H, J=6.0 Hz).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol)and 1-phenylethan-1-one (774 mg, 6.44 mmol) in methanol (30 mL) wasadded NaBH₃CN (511 mg, 8.13 mmol). The resulting solution was stirred at50° C. overnight. Water (50 mL) was added. Methanol was stripped offunder vacuum. The remaining solution was extracted with ethyl acetate(×2). The organic layers were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel column eluting with ethylacetate/petroleum ether (1:1). This resulted in 750 mg (48%) oftert-butyl 4-(1-phenylethyl)piperazine-1-carboxylate as yellow oil. LCMS(Method 20) [M+H]⁺=291.1, R_(T)=1.14 min.

A solution of tert-butyl 4-(1-phenylethyl)piperazine-1-carboxylate (750mg, 2.58 mmol) and saturated HCl dioxane solution (20 mL) was stirred atroom temperature for 3 h. The solids were collected by filtration anddried. This resulted in 320 mg (55%) of 1-(1-phenylethyl)piperazinehydrochloride as a white solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (4 mL) was added 1-(1-phenylethyl)piperazinehydrochloride (47 mg, 0.21 mmol), DIEA (67 mg, 0.52 mmol), HATU (79.2mg, 0.21 mmol). The resulting mixture was stirred at room temperatureovernight and concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-005): Column,XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with10 mmol NH4HCO3 and MeCN (40.0% up to 65.0% in 10 min, up to 95.0% in 1min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220nm. This resulted in 31.3 mg (28%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 21) [M+H]⁺=635.0, R_(T)=1.56 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.67 (d, 1H, J=4.8 Hz), 8.28 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),7.53 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.35-7.26 (m, 6H), 7.07(t, 1H, J=73.2 Hz), 5.19 (s, 2H), 3.49-3.46 (m, 5H), 2.49-2.33 (m, 4H),1.31 (d, 3H, J=6.4 Hz).

Example 317

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(2-methylpropyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid and 1-(2-methylpropyl)piperazine. LCMS (Method 25) [M+H]⁺=587.1,R_(T)=1.80 min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.33(dd, 1H, J=1.8, 6.9 Hz), 8.68 (dd, 1H, J=1.5, 3.9 Hz), 8.67 (s, 1H),8.31 (s, 1H), 7.62 (dd, 1H, J=3.0, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45(d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.02 (t, 1H, J=73.2Hz), 5.23 (s, 2H), 3.57-3.42 (m, 4H), 2.40-2.21 (m, 4H), 2.05 (d, 2H,J=7.2 Hz), 1.81-1.76 (m, 1H), 0.86 (d, 6H, J=6.3 Hz).

Example 318

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazol[1,5-a]pyrimidine-3-carboxamide

To a solution of 3-methyloxetane-3-carbaldehyde (17.2 mg, 0.17 mmol) andN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.13 mmol) in methanol (5 mL) was added NaBH₃CN (12.5 mg, 0.20mmol). The resulting solution was stirred at room temperature overnight.The reaction was then quenched by the addition of 5 mL of water. Theresulting mixture was concentrated under vacuum. The residue wasdissolved in ethyl acetate (30 mL), washed with brine, dried andconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBDColumn, 5 um, 19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃ andMeCN (55.0% up to 65.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1min, down to 55.0% in 2 min); Detector, UV 254/220 nm. This resulted in39.8 mg (49%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide.LCMS (Method 25) [M+H]⁺=615.2, R_(T)=0.93 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 9.92 (s, 1H), 9.36-9.27 (m, 1H), 8.91-8.68 (m, 2H), 8.31 (s,1H), 7.73-7.46 (m, 3H), 7.37-7.06 (m, 2H), 5.23 (s, 2H), 4.52-4.20 (m,4H), 3.60-3.11 (m, 6H), 2.43-2.20 (m, 4H), 1.46 (s, 3H).

Example 319

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-propylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 1-propylpiperazine dihydrobromide (60.4 mg, 0.21 mmol)and{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (2 mL) was added DIEA (112 mg, 0.866 mmol), HATU(79.2 mg, 0.21 mmol). The resulting solution was stirred at roomtemperature overnight and concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 10 mmol NH4HCO3 and MeCN (50.0% up to 61.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 50.0% in 2 min); Detector,UV 254/220 nm. This resulted in 69.1 mg (70%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-propylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=573.2, R_(T)=2.86 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz),8.68 (dd, 1H, J=1.6, 7.6 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.62 (dd, 1H,J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28(dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.6 Hz), 5.23 (s, 2H), 3.48 (t,4H, J=6.0 Hz), 2.40-2.34 (m, 4H), 2.24 (t, 2H, J=7.2 Hz), 1.48-1.41 (m,2H), 0.85 (t, 3H, J=7.2 Hz).

Example 320

N-[1-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]aceticacid (100 mg, 0.17 mmol) in DMF (4 mL) and 1-benzylpiperazine (33.6 mg,0.19 mmol) was added DIEA (44.8 mg, 0.35 mmol), HATU (79.2 mg, 0.21mmol). The resulting solution was stirred at room temperature overnight.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 10 mmol NH₄HCO₃ and MeCN (37.0% MeCN up to 50.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 37.0% in 2 min);Detector, UV 254/220 nm. This resulted in 53.8 mg (50%) ofN-[1-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 21) [M+H]⁺=621.0, R_(T)=1.53 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55(d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.65-7.24 (m, 6H), 7.08 (t,1H, J=73.2 Hz), 5.23 (m, 2H), 3.52-3.46 (m, 6H), 2.49-2.33 (m, 4H).

Example 321

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) and 4-[2-(piperazin-1-yl)ethyl]morpholine (41 mg, 0.21mmol) in DMF (5 mL) was added DIEA (45 mg, 0.35 mmol), HATU (79 mg, 0.21mmol). The resulting solution was stirred at room temperature for 3 h.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 10 mmol NH₄HCO₃ and MeCN (37.0% MeCN up to 52.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 37.0% in 2 min);Detector, UV 254/220 nm. This resulted in 62.0 mg (56%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=644.2, R_(T)=2.34 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d,1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.09 (t, 1H, J=73.6 Hz), 5.23 (s, 2H), 3.54 (t, 4H, J=4.4 Hz), 3.50-3.46(m, 4H), 2.49-2.39 (m, 12H).

Example 322

methyl2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1l-yl]acetyl)piperazin-1-yl]acetate

To a solution of tert-butyl piperazine-1-carboxylate (5 g, 26.85 mmol)in DMF (50 mL) was added and Cs₂CO₃ (11 g, 33.76 mmol) and methyl2-bromoacetate (3.4 g, 22.2 mmol). The resulting mixture was stirred atroom temperature for 6 h. Water (50 mL) and DCM (100 mL) was added.Phases were separated. The aqueous phase was extracted with DCM (100mL). The combined organic phases were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in7.1 g (crude) of tert-butyl4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as yellow oil. LCMS(Method 27) [M+H]⁺=259.2, R_(T)=1.08 min.

A solution of tert-butyl4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.50 g, 5.81 mmol) andsaturated HCl dioxane solution (20 mL) was stirred at room temperaturefor 3 h. The solids were collected by filtration and dried. Thisresulted in 950 mg (84%) of methyl 2-(piperazin-1-yl)acetatehydrochloride as a white solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (2 mL) was added methyl 2-(piperazin-1-yl)acetatehydrochloride (41 mg, 0.21 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2mg, 0.21 mmol). The resulting solution was stirred at room temperaturefor 2 h and concentrated under vacuum. The residue was passed through ashort pad of silica gel eluting with 10% MeOH in DCM. The crude productwas purified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 10 mmol NH₄HCO₃ and MeCN (40.0% up to 59.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector,UV 254/220 nm. This resulted in 49.2 mg (47%) of methyl2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetateas a white solid. LCMS (Method 20) [M+H]⁺=603.2, R_(T)=2.83 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d,1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.63 (s, 3H), 3.52-3.48 (m, 4H),3.30 (s, 2H), 2.67-2.51 (m, 4H).

Example 323

N-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-1-[(5-oxooxolan-2-yl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A 8-mL microwave tube was charged withN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.37 mmol), 5-(chloromethyl)oxolan-2-one (74.6 mg, 0.55 mmol),Cs₂CO₃ (242 mg, 0.74 mmol) in DMF (2 mL). The vessel was evacuated undervacuum and refilled with nitrogen 3 times. The final reaction mixturewas irradiated with microwave radiation at 120° C. for 30 min. Theresulting mixture was concentrated under vacuum. The residue was passedthrough a short pad of silica gel eluting with ethyl acetate. The crudeproduct was purified by Prep-HPLC with the following conditions(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm;mobile phase, water with 0.05% FA and MeCN (39.0% up to 53.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 39.0% in 2 min);Detector, UV 254/220 nm. This resulted in 35.8 mg (19%) ofN-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-1-[(5-oxooxolan-2-yl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=503.1, R_(T)=1.65 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz),8.68-8.66 (m, 2H), 8.38 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.61 (d,1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz),7.00 (t, 1H, J=73.2 Hz), 4.98-4.94 (m, 1H), 4.48 (d, 2H, J=5.1 Hz),2.46-2.23 (m, 3H), 2.07-1.98 (m, 1H).

Example 324

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (200 mg) in DMF (5 mL) was added tert-butylpiperazine-1-carboxylate (77.5 mg, 0.42 mmol), DIEA (89.6 mg, 0.69mmol), HATU (158.3 mg, 0.42 mmol). The resulting solution was stirred atroom temperature for 3 h and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with 3% MeOH inDCM to afford 279 mg of tert-butyl4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylateas a yellow solid. LCMS (Method 22) [M+H]⁺=631.4, R_(T)=1.49 min.

A solution of tert-butyl4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate(279 mg, 0.44 mmol) and saturated HCl dioxane solution (10 mL) wasstirred at room temperature overnight. The reaction mixture wasconcentrated under vacuum. The residue was redissolved in methanol andneutralized with DIEA. The neutralized solution was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃ and MeCN (35.0% MeCNup to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, downto 35.0% in 2 min); Detector, UV 254/220 nm. This resulted in 95.6 mg(41%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=531.2, R_(T)=2.67 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz),8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d,1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 5.22 (s, 2H), 3.47-3.41 (m, 4H), 2.73-2.67 (m,4H).

Example 325

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol) inDMF (15 mL) was added Cs₂CO₃ (3.5 g, 10.74 mmol),2-bromo-N,N-dimethylacetamide (1.80 g, 10.84 mmol). The resultingmixture was stirred at room temperature overnight. Water (40 mL) andEtOAc (100 mL) was added. Phases were separated. The aqueous phase wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 3% MeOH in DCM. This resulted in 880 mg (60%) of tert-butyl4-[(dimethylcarbamoyl)methyl]piperazine-1-carboxylate as yellow oil.TLC: R_(f)=0.3; dichloromethane/methanol=1/10.

A solution of tert-butyl4-[(dimethylcarbamoyl)methyl]piperazine-1-carboxylate (880 mg, 3.24mmol) and saturated HCl dioxane solution (20 mL) was stirred at roomtemperature overnight. The solids were collected by filtration. Thisresulted in 450 mg (67%) of N,N-dimethyl-2-(piperazin-1-yl)acetamidehydrochloride as a white solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (4 mL) was addedN,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72 mg, 0.35mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-005): Column, XBridge Prep C18OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN(27.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min,down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 73.4mg (64%) of the formic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 20) [M+H]⁺=616.3, R_(T)=2.41 min.¹HNMR (400 MHz, CD₃OD-d₄) δ: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz),8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8 Hz),7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H,J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H), 3.84-3.77 (m,4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m, 7H).

Example 326

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(2-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

NaBH₃CN (112 mg, 1.78 mmol) was added portionwise to a solution of2-hydroxybenzaldehyde (55 mg, 0.45 mmol) andN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.45 mmol) in methanol (10 mL). The resulting solutionwas stirred at room temperature overnight. The reaction was thenquenched by the addition of 0.5 mL of water. The resulting mixture wasconcentrated under vacuum. The residue was passed through a short pad ofsilica gel eluting with 3% MEOH in DCM. The crude product was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-005): Column,XBridge Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase, water with10 mmol NH₄HCO₃ and MeCN (38.0% up to 45.0% in 10 min, up to 95.0% in 1min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220nm. This resulted in 28.8 mg (12%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(2-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=554.2, R_(T)=2.79 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.0 Hz), 7.61 (d,1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),7.09-7.04 (m, 2H), 7.06 (t, 1H, J=73.6 Hz), 6.73-6.69 (m, 2H), 4.29 (t,2H, J=6.0 Hz), 3.82 (s, 2H), 2.98 (t, 2H, J=6.0 Hz).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

NaBH₃CN (28 mg, 0.45 mmol) was added to a solution ofN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.22 mmol) in MeOH (10 mL) and 3-hydroxybenzaldehyde (55 mg,0.45 mmol). The resulting solution was stirred for at room temperatureovernight. The reaction was then quenched by the addition of 0.2 mL ofwater. The resulting mixture was concentrated under vacuum. The residuewas passed through a short pad of silica gel eluting with 2.5% MeOH inDCM. The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% FA and MeCN (32.0% up to 36.0%in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 32.0% in 2min); Detector, UV 254/220 nm. This resulted in 25.7 mg (19%) of theformic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideformate as a white solid. LCMS (Method 20) [M+H]⁺=554.2, R_(T)=1.58 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.37 (s, 1H), 9.34 (dd, 1H, J=1.6,7.2 Hz), 8.68-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.4, 8.8 Hz),7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2Hz), 7.05 (t, 1H, J=73.2 Hz), 7.10-7.06 (m, 1H), 6.74-6.72 (m, 2H), 6.60(d, 1H, J=7.2 Hz), 4.25 (t, 2H, J=6.0 Hz), 3.66 (s, 2H), 2.94 (t, 2H,J=6.0 Hz).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of 4-hydroxybenzaldehyde (55 mg, 0.45 mmol) andN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.22 mmol) in THF (10 mL) was stirred at room temperature for 2h and then NaBH₃CN (28 mg, 0.45 mmol) was added. The resulting solutionwas stirred at room temperature overnight. The reaction was thenquenched by the addition of 0.1 mL of water. The resulting mixture wasconcentrated under vacuum. The residue was passed through a short pad ofsilica gel eluting with 3% MeOH in DCM. The crude product was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-005): Column,XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with0.05% FA and MeCN (34.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV 254/220nm. This resulted in 31.4 mg (23%) of the formic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 20) [M+H]⁺=554.2, R_(T)=1.58 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60(d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),7.10 (d, 2H, J=8.4 Hz), 7.06 (t, 1H, J=73.2 Hz), 6.68 (d, 2H, J=8.4 Hz),4.25 (t, 2H, J=6.4 Hz), 3.63 (s, 2H), 2.95 (t, 2H, J=6.0 Hz).

methyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetateformate

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (500 mg) in DMF (10 mL) was added tert-butylN-(piperidin-4-yl)carbamate (208 mg, 1.04 mmol), DIEA (224 mg, 1.73mmol), HATU (395.9 mg, 1.04 mmol). The resulting solution was stirred atroom temperature overnight. Water (50 mL) was added. The precipitateswere collected by filtration and dried. This resulted in 600 mg oftert-butylN-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]carbamate as a yellow crude solid. LCMS (Method 25)[M+H]⁺=645.1, R_(T)=1.02 min.

A solution of the crude product from previous step (600 mg) andsaturated HCl dioxane solution (15 mL) was stirred at room temperatureovernight. The resulting solution was diluted with 100 mL of methanoland neutralized with saturated aqueous.Na₂CO₃ and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 30% MeOH in DCM. Collection of appropriate fractions andevaporation of solvent affordedN-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(520 mg) as a yellow solid. LCMS (Method 25) [M+H]⁺=545.1, R_(T=)0.62min.

Methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added to a mixture ofN-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.18 mmol) in DMF (5 mL) and potassium carbonate (38.1 mg, 0.28mmol). The resulting mixture was stirred at room temperature overnight.Additional amount of methyl 2-bromoacetate (30.74 mg, 0.20 mmol) wasadded and the resulting solution was stirred at 60° C. for 2 h. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% FA and MeCN (25.0% MeCN up to 32.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector,UV 254/220 nm. This resulted in 68.9 mg (57%) of the formic acid salt ofmethyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetateas an off-white solid. LCMS (Method 24) [M+H]⁺=617.2, R_(T)=1.53 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 dd, 1H, J=1.6, 7.2Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55(d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 5.23-5.20 (m, 2H), 4.11-4.07 (m, 1H), 3.83-3.80(m, 1H), 3.63 (s, 3H), 3.39-3.31 (m, 2H), 3.15-3.12 (m, 1H), 2.87-2.83(m, 1H), 2.71-2.67 (m, 1H), 1.83-1.77 (m, 2H), 1.29-1.14 (m, 2H).

Example 330

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideformate

DIEA (71 mg, 0.55 mmol) was adde to a solution ofN-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.18 mmol) and (5-oxooxolan-2-yl)methyltrifluoromethanesulfonate (69 mg, 0.28 mmol) in CH₃CN (30 mL). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% FA and MeCN (38.0% up to 46.0% in 10 min, up to 95.0%in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV254/220 nm. This resulted in 41.6 mg (33%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 25) [M+H]⁺=643.2, R_(T)=1.49 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.6, 6.8Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56(d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz),7.09 (t, 1H, J=73.2 Hz), 5.26-5.24 (m, 2H), 4.89 (br, 1H), 4.59-4.45 (m,2H), 4.08-3.90 (m, 2H), 3.25-2.97 (m, 3H), 2.68-2.58 (m, 1H), 2.46-2.21(m, 2H), 1.86-1.65 (m, 3H), 1.57-1.50 (m, 3H).

Example 331

methyl3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate

To a solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol) inDMF (20 mL) was added Cs₂CO₃ (589 mg, 1.81 mmol) and methyl3-bromopropanoate (744 mg, 4.46 mmol). The resulting mixture was stirredat room temperature overnight. Water (50 m) and EtOAc (50 mL) was added.Phases were separated. The aqueous phase was extracted with EtOAc (50mL). The organic layers were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by falsh chromatography on silica gel eluting with 3.5% MeOH inDCM. Collection of appropriate fractions and evaporation of solventafforded tert-butyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate(895 mg, 74%) as yellow oil. TLC: R_(f)=0.3; ethyl acetate/petroleumether=1/2.

A solution of tert-butyl4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (895 mg, 3.29 mmol)and saturated HCl dioxane solution (15 mL) was stirred at roomtemperature overnight. The solids were collected by filtration. Thisresulted in 710 mg of methyl 3-(piperazin-1-yl)propanoate hydrochlorideas a white crude solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (5 mL) was added methyl3-(piperazin-1-yl)propanoate hydrochloride (44 mg, 0.21 mmol), DIEA (90mg, 0.70 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution wasstirred at room temperature for 4 h and concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions(Prep-HPLC-005): Column, XBridge Prep C₁₈ OBD Column, 5 um, 19*150 mm;mobile phase, water with 0.05% FA and MeCN (40.0% up to 51.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min);Detector, UV 254/220 nm. This resulted in 56.1 mg (49%) of the formicacid salt of methyl3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoateas a light yellow solid. LCMS (Method 25) [M+H]⁺=617.1, R_(T)=1.51 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6,7.2 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.60 (s, 3H), 3.49-3.41 (m,4H), 2.59 (t, 2H, J=6.4 Hz), 2.51 (t, 2H, J=6.4 Hz), 2.39-2.33 (m, 4H).

Example 332

3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate

Using synthetic methods analoguous to that of methyl3-[4-(2-[3-[5chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate,the title compound was prepared from ethyl 3-bromopropanoate. LCMS(Method 28) [M+H]⁺=631.2, R_(T)=0.89 min. ¹H NMR (300 MHz, DMSO-d₆) δ:(ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9 Hz), 8.69-8.67 (m, 2H), 8.30 (s,1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H,J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.07 (t, 1H, J=72.9 Hz), 5.23(s, 2H), 4.03 (q, 2H, J=7.2 Hz), 3.59-3.47 (m, 4H), 2.61-2.59 (m, 2H),2.50-2.33 (m, 6H), 1.16 (t, 3H, J=7.2 Hz).

Example 333

methyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazzolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate

To a stirring solution of tert-butyl4-(2-hydroxyethyl)piperazine-1-carboxylate (1.5 g, 6.51 mmol) and DIEA(2.5 g, 19.34 mmol) in DCM (50 mL) was added MsCl (817 mg, 7.13 mmol)dropwise g at 0° C. The resulting solution was stirred for 1 h at roomtemperature. Water (100 mL) wsa added. Phases were separated. Theaqueous phase was extracted with dichloromethane and the organic layerscombined. The organic phases were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in1.8 g (crude) of tert-butyl4-[2-(methanesulfonyloxy)ethyl]piperazine-1-carboxylate as light yellowoil.

To a solution of tert-butyl4-[2-(methanesulfonyloxy)ethyl]piperazine-1-carboxylate (431 mg, 1.39mmol) in DMF (5 mL) was added methyl piperidine-4-carboxylate (300 mg,2.095 mmol) and DIEA (361 mg, 2.79 mmol). The resulting solution wasstirred at room temperature overnight. The resulting mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 3% MeOH in DCM. This resultedin 285 mg (57%) of tert-butyl4-[2-[4-(methoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylateas yellow oil. LCMS (Method 20) [M+H]⁺=356.2, R_(T)=0.99 min.

A solution of tert-butyl4-[2-[4-(methoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate(285 mg, 0.80 mmol) and saturated HCl dioxane solution (15 mL) wasstirred at room temperature overnight. The resulting mixture wasconcentrated under vacuum. This resulted in 205 mg (88%) of methyl1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride as ayellow solid. LCMS (Method 20) [M+H]⁺=256.2, R_(T)=0.44 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was added methyl1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (190mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The residue was passed through a short pad ofsilica gel eluting with 4% MeOH in DCM. The crude product was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-005): Column,XBridge Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase, water with0.05% FA and MeCN (22.0% up to 31.0% in 10 min, up to 95.0% in 1 min,hold 95.0% in 1 min, down to 22.0% in 2 min); Detector, UV 254/220 nm.This resulted in 96.5 mg (40%) of the formic acid salt of methyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylateas a light yellow solid. LCMS (Method 24) [M+H]⁺=700.2, R_(T)=2.21 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6,6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.59 (s, 3H), 3.49-3.46 (m,4H), 2.84-2.81 (m, 2H), 2.54-2.52 (m, 6H), 2.50-2.40 (m, 2H), 2.33-2.27(m, 1H), 2.04-1.99 (m, 2H), 1.88-1.70 (m, 2H), 1.55-1.50 (m, 2H).

Example 334

ethyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate

To a solution of tert-butyl4-[2-(methanesulfonyloxy)ethyl]piperazine-1-carboxylate (392 mg, 1.27mmol) in DMF (5 mL) was added DIEA (329 mg, 2.55 mmol) and ethylpiperidine-4-carboxylate (300 mg, 1.91 mmol). The resulting solution wasstirred at room temperature overnight and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with5% MeOH in DCM. This resulted in 310 mg (66%) of tert-butyl4-[2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate asa yellow solid. LCMS (Method 28) [M+H]⁺=370.3, R_(T)=0.50 min.

A mixture of tert-butyl4-[2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate(310 mg, 0.84 mmol) and saturated HCl dioxane solution (15 mL) wasstirred at room temperature overnight. The resulting mixture wasconcentrated under vacuum. This resulted in 220 mg (86%) of ethyl1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride as alight yellow solid. LCMS (Method 28) [M+H]⁺=270.3, R_(T)=0.89 min.

To a solution of2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was added ethyl1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (199mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The residue was passed through a short pad ofsilica gel eluting with 3% MeOH in DCM. The crude product was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-005): Column,XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with0.05% FA and MeCN (18.0% MeCN up to 27.0% in 10 min, up to 95.0% in 1min, hold 95.0% in 1 min, down to 18.0% in 2 min); Detector, UV 254/220nm. This resulted in 66.1 mg (27%) of the formic acid salt of ethyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate.LCMS (Method 24) [M+H]⁺=714.2, R_(T)=2.42 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H),8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.46(d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2Hz), 5.23 (m, 2H), 4.03 (q, 2H, J=6.8 Hz), 3.50-3.47 (m, 4H), 2.88-2.85(m, 2H), 2.52-2.51 (m, 6H), 2.47-2.26 (m, 3H), 2.12-2.07 (m, 2H),1.80-1.78 (m, 2H), 1.60-1.55 (m, 2H), 1.16 (t, 3H, J=7.2 Hz). □

Example 335

methyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]-4-methylpiperidine-4-carboxylateformate

Using synthetic method analoguous to that of ethyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate,the title compound was prepared from methyl4-methylpiperidine-4-carboxylate hydrochloride.

LCMS (Method 24) [M+H]⁺=714.2, R_(T)=1.94 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H),8.30 (s, 1H), 7.65-7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz),7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H,J=73.6 Hz), 5.22 (s, 2H), 3.62 (s, 3H), 3.48-3.45 (m, 4H), 2.57-2.51 (m,2H), 2.49-2.39 (m, 8H), 2.01-1.93 (m, 4H), 1.41-1.35 (m, 2H), 1.10 (s,3H). □

Example 336

2-(morpholin-4-yl)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate

To a solution of 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid(1.00 g, 4.36 mmol) in DCM (15 mL) was added2-(morpholin-4-yl)ethan-1-ol (858 mg, 6.54 mmol), EDC.HCl (1.00 g, 5.22mmol), 4-dimethylaminopyridine (53.3 mg, 0.44 mmol). The resultingsolution was stirred at room temperature overnight. Water (30 mL) andDCM (50 mL) was added. Phases were separated. The aqueous phase wasextracted with DCM and the organic layers combined. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/ethyl acetate(2:3). This resulted in 1.4 g (crude) of 1-tert-butyl4-[2-(morpholin-4-yl)ethyl]piperidine-1,4-dicarboxylate as yellow oil.TLC: R_(f)=0.3; ethyl acetate.

A mixture of 1-tert-butyl4-[2-(morpholin-4-yl)ethyl]piperidine-1,4-dicarboxylate (1.4 g, 4.09mmol) and saturated HCl dioxane solution (20 mL) was stirred at roomtemperature overnight. The resulting mixture was concentrated undervacuum. This resulted in 1.2 g (crude) of 2-(morpholin-4-yl)ethylpiperidine-4-carboxylate hydrochloride as yellow oil.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.26 mmol) in DMF (2 mL) was added 2-(morpholin-4-yl)ethylpiperidine-4-carboxylate hydrochloride (140 mg, 0.50 mmol), DIEA (101mg, 0.78 mmol), HATU (119 mg, 0.31 mmol). The resulting solution wasstirred at room temperature overnight and concentrated under vacuum. Theresidue was passed through a short pad of silica gel eluting with 10%MeOH in DCM. The crude product was purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBDColumn, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN(31.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1min, down to 31.0% in 2 min); Detector, UV 254/220 nm. This resulted in35.6 mg (20%) of the formic acid salt of 2-(morpholin-4-yl)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylateas a off-white solid. LCMS (Method 28) [M+H]⁺=687.2, R_(T)=0.86 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55(d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 5.27-5.22 (m, 2H), 4.20-4.15 (m, 3H), 3.89-3.82(m, 1H), 3.58-3.55 (m, 4H), 3.26-3.17 (m, 1H), 2.89-2.78 (m, 1H),2.69-2.59 (m, 1H), 2.53-2.51 (m, 2H), 2.40-2.32 (m, 4H), 1.91-1.80 (m,2H), 1.69-1.41 (m, 2H).

Example 337

ethyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]-4-methylpiperidine-4-carboxylateformate

Using synthetic method analoguous to that of ethyl1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate,the title compound was prepared from ethyl4-methylpiperidine-4-carboxylate hydrochloride. LCMS (Method 24)[M+H]⁺=728.2, R_(T)=1.87 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.75(s, 1H), 9.34 (dd, 1H, J=1.2, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H),7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.22 (s,2H), 4.06 (q, 2H, J=7.2 Hz), 2.67-2.60 (m, 2H), 2.44-2.38 (m, 8H),2.09-2.04 (m, 2H), 1.97-1.93 (m, 2H), 1.42-1.41 (m, 2H), 1.16 (t, 3H,J=7.2 Hz), 1.10 (s, 3H).

Example 338

2-(dimethylamino)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate

Using synthetic method analoguous to that of 2-(morpholin-4-yl)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate,the title compound was prepared from 2-(dimethylamino)ethan-1-ol. LCMS(Method 24) [M+H]⁺=645.2, R_(T)=2.97 min. ¹H NMR (400 MHz, DMSO-d₆) δ:(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.67 (m, 2H),8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45(d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.21 (t, J=73.1 Hz, 1H)5.30-5.14 (m, 2H), 4.21-4.10 (m, 3H), 3.89-3.78 (m, 1H), 3.24-3.14 (m,1H), 2.89-2.60 (m, 2H), 2.49-2.45 (m, 2H), 2.16 (s, 6H), 1.89-1.81 (m,2H), 1.68-1.37 (m, 2H).

Example 339

2-(morpholin-4-yl)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate

To a solution of1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (1.00 g,4.11 mmol) in DCM (10 mL) was added 2-(morpholin-4-yl)ethan-1-ol (1.08g, 8.23 mmol), HOBt (667 mg, 4.94 mmol). The mixture was stirred at roomtemperature for 2 hr, then EDC.HCl (943 mg, 4.92 mmol) was added. Theresulting solution was stirred at room temperature overnight and dilutedwith 30 mL of DCM. The resulting mixture was washed with water, brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with4% MeOH in DCM. This resulted in 800 mg (55%) of 1-tert-butyl4-[2-(morpholin-4-yl)ethyl]4-methylpiperidine-1,4-dicarboxylate asyellow oil. LCMS (Method 28) [M+H]⁺=357.2, R_(T)=0.64 min.

A solution of 1-tert-butyl4-[2-(morpholin-4-yl)ethyl]4-methylpiperidine-1,4-dicarboxylate (800 mg,2.24 mmol) and saturated HCl dioxane solution (30 mL) was stirred atroom temperature overnight. The resulting mixture was concentrated undervacuum. This resulted in 600 mg (crude) of 2-(morpholin-4-yl)ethyl4-methylpiperidine-4-carboxylate hydrochloride as a white crude solid.LCMS (Method 28) [M+H]⁺=257.0, R_(T)=0.86 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (3 mL) was added 2-(morpholin-4-yl)ethyl4-methylpiperidine-4-carboxylate hydrochloride (76.2 mg, 0.26 mmol),DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resultingsolution was stirred at room temperature overnight and concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-005): Column, XBridge Prep C₁₈ OBDColumn, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN(34.0% up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min,down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 43.0mg (33%) of the formic acid salt of2-(morpholin-4-yl)ethyll-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)-4-methylpiperidine-4-carboxylate. LCMS (Method 20) [M+H]+=701.2, R_(T)=0.92 min.1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.6,7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz),7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.6 Hz), 7.29 (dd, 1H, J=4.4, 6.8Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 4.21 (t, 2H, J=5.6 Hz),4.02-3.98 (m, 1H), 3.77-3.74 (m, 1H), 3.53-3.51 (m, 4H), 3.27-3.22 (m,1H), 3.00-2.94 (m, 1H), 2.55-2.52 (m, 2H), 2.49-2.39 (m, 4H), 2.04-1.97(m, 2H), 1.18 (s, 3H).

Example 340

2-(dimethylamino)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1l-yl]acetyl)-4-methylpiperidine-4-carboxylate

To a solution of1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (1 g,4.11 mmol) in DCM (10 mL) was added 2-(dimethylamino)ethan-1-ol (733 mg,8.22 mmol), HOBt (667 mg, 4.94 mmol). The mixture was stirred at roomtemperature for 2 h, then EDC.HCl (943 mg, 4.92 mmol) was added. Theresulting solution was stirred at room temperature overnight and water(30 mL) was added. The resulting solution was extracted with DCM (×2)and the organic layers combined. The organic phase was washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 4% MeOH in DCM. This resulted in 800 mg (62%) of1-tert-butyl4-[2-(dimethylamino)ethyl]4-methylpiperidine-1,4-dicarboxylate as yellowoil. TLC: R_(f)=0.3; dichloromethane/methanol=10/1.

A mixture of 1-tert-butyl4-[2-(dimethylamino)ethyl]4-methylpiperidine-1,4-dicarboxylate (800 mg,2.54 mmol) and saturated HCl dioxane solution (20 mL) was stirred atroom temperature overnight. The resulting mixture was concentrated undervacuum. This resulted in 340 mg (53%) of 2-(dimethylamino)ethyl4-methylpiperidine-4-carboxylate hydrochloride as a white solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (3 mL) was added 2-(dimethylamino)ethyl4-methylpiperidine-4-carboxylate hydrochloride (87 mg, 0.35 mmol), DIEA(67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solutionwas stirred at room temperature overnight and concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C₁₈ OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN up to42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 49.7 mg (41%)of the formic acid salt of 2-(dimethylamino)ethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate.LCMS (Method 28) [M+H]⁺=659.2, R_(T)=1.23 min. ¹H NMR (400 MHz, DMSO-d₆)δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H),8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46(d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2Hz), 5.23 (s, 2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71(m, 1H), 3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33(s, 6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).

Example 341

piperidin-4-ylmethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate

To a solution of1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylicacid (150 mg, 0.26 mmol) in DMF (5 mL) was added tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (281 mg, 1.31 mmol),4-dimethylaminopyridine (10 mg, 0.08 mmol), HATU (120 mg, 0.32 mmol).The resulting solution was stirred at room temperature overnight. ThenDIEA (68 mg, 0.53 mmol) was added. The resulting solution was stirredfor an additional 3 h at room temperature and concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith 3% MeOH in DCM. This resulted in 150 mg (74%) of[1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylateas yellow oil. LCMS (Method 28) [M+H]⁺=771.2, R_(T=)1.10 min.

A solution of [1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate(150 mg, 0.19 mmol) and saturated HCl dioxane solution (10 mL) wasstirred at room temperature overnight. The resulting mixture wasconcentrated under vacuum. The resulting solution was diluted with 10 mLof methanol. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm;mobile phase, water with 0.05% FA and MeCN (30.0% up to 33.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min);Detector, UV 254/220 nm. This resulted in 82.3 mg (59%) of the formicacid salt of piperidin-4-ylmethyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylateas a light yellow solid. LCMS (Method 20) [M+H]⁺=671.3, R_(T)=1.58 min.¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.2,6.9 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz),7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.5, 7.2Hz), 7.01 (t, 1H, J=73.5), 5.25-5.23 (m, 2H), 4.24-4.19 (m, 1H),3.93-3.85 (m, 3H), 2.83-2.80 (m, 1H), 2.72-2.64 (m, 3H), 1.92-1.87 (m,3H), 1.71-1.67 (m, 3H), 1.59-1.48 (m, 1H), 1.44-1.23 (m, 2H).

Example 342

1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylicacid

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (500 mg, 1.08 mmol) in DMF (5 mL) was added methylpiperidine-4-carboxylate (232.1 mg, 1.62 mmol), DIEA (279.2 mg, 2.16mmol), HATU (493.5 mg, 1.30 mmol). The resulting solution was stirred atroom temperature overnight. The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 3% MeOH in DCM. This resulted in 500 mg (79%) of methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylateas yellow oil. LCMS (Method 25) [M+H]⁺=588.1, R_(T)=0.87 min.

K₂CO₃ (500 mg, 3.59 mmol) in H₂O (5 mL) was added to methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate(500 mg, 0.85 mmol) in methanol (10 mL). The resulting solution wasstirred at 50° C. overnight and acidified with 1 N HCl to pH 2. Thesolids were collected by filtration. The crude product was purified byPrep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridgePrep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FAand MeCN (30.0% MeCN up to 34.0% in 10 min, up to 95.0% in 1 min, hold95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. Thisresulted in 390 mg (80%) of1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidine-4-carboxylicacid as a light yellow solid. LCMS (Method 28) [M+H]⁺=574.1, R_(T)=1.11min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 12.34 (s, 1H), 9.76 (s, 1H),9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd,1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28(dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.29-5.19 (m, 2H),4.28-4.18 (m, 1H), 3.87-3.84 (m, 1H), 3.19-3.13 (m, 1H), 2.83-2.77 (m,1H), 1.86-1.85 (m, 2H), 1.60-1.57 (m, 1H), 1.43-1.41 (m, 2H).

Example 343

1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylicacid

To a solution of2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]aceticacid (500 mg, 1.08 mmol) in DMF (4 mL) was added methyl4-methylpiperidine-4-carboxylate (275 mg, 1.75 mmol), DIEA (419 mg, 3.24mmol), HATU (494 mg, 1.30 mmol). The resulting solution was stirred for4 h at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 3% MEOH in DCM. This resulted in 500 mg (77%) of methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylateas yellow oil. LCMS (Method 25) [M+H]⁺=602.1, R_(T)=0.92 min.

To a solution of methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate(500 mg, 0.83 mmol) in methanol (10 mL) was added a solution ofpotassium carbonate (700 mg, 5.06 mmol) in water (5 mL). The resultingsolution was stirred at 60° C. overnight and acidified with 1 N HCl topH 2. The solids were collected by filtration. The crude product waspurified by Prep-HPLC with the following conditions (Prep-HPLC-005):Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% FA and MeCN (30.0% MeCN up to 35.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector,UV 254/220 nm. This resulted in 26.6 mg of1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylicacid as a white solid. LCMS (Method 20) [M+H]⁺=588.2, R_(T)=2.79 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 12.5 (br, 1H), 9.76 (s, 1H), 9.34 (d,1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H,J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.28-5.18 (m, 2H), 3.96-3.93(m, 1H), 3.74-3.70 (m, 1H), 3.26-3.23 (m, 1H), 3.01-2.95 (m, 1H),1.98-1.93 (m, 2H), 1.46-1.30 (m, 2H), 1.18 (s, 3H).

Example 344

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a cold solution of 5-(hydroxymethyl)oxolan-2-one (100 mg, 0.86 mmol),DIEA (340 mg, 2.63 mmol) in DCM (5 mL) was added Tf₂O (247 mg, 0.88mmol) at 0° C. The resulting solution was stirred at room temperaturefor 3 h and quenched with saturated Na₂CO₃ solution. The resultingsolution was extracted with dichloromethane (×3) and the organic layerscombined. The combined organic layers were washed with brine., driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 180 mg (84%) of (5-oxooxolan-2-yl)methyltrifluoromethanesulfonate as yellow oil.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.18 mmol) in CH₃CN (5 mL) was added DIEA (70 mg, 0.54 mmol)and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate (66.5 mg, 0.27mmol). The resulting solution was stirred overnight at room temperature.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 36.0%in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2min); Detector, UV 254/220 nm. This resulted in 37 mg (31%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LCMS (Method 24) [M+H]⁺=657.2, R_(T)=1.68 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 7.2 Hz),8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d,1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz),7.09 (t, 1H, J=73.2 Hz), 5.24-5.17 (m, 2H), 4.58-4.54 (m, 1H), 4.41-4.38(m, 1H), 3.98-3.95 (m, 1H), 3.16-3.03 (m, 1H), 2.69-2.55 (m, 4H),2.46-2.44 (m, 2H), 2.26 (s, 3H), 2.24-2.16 (m, 1H), 1.88-1.83 (m, 1H),1.79-1.71 (m, 2H), 1.48-1.44 (m, 1H), 1.29-1.21 (m, 1H).

methyl3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoate

To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.00 g,4.99 mmol) in CH₃CN (20 mL) was added potassium carbonate (1.38 g, 9.99mmol) and methyl 3-bromopropanoate (3.34 g, 20.00 mmol). The resultingsolution was heated to reflux for 20 h and cooled to room temperature.Water (100 mL) and DCM (100 mL) was added. Phases were separated. Theaqueous phase was extracted with DCM. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with 4% MeOH in DCM. This resulted in 300 mg (21%) oftert-butyl 4-[(3-methoxy-3-oxopropyl)amino]piperidine-1-carboxylate asyellow oil. LCMS (Method 20) [M+H]⁺=287.0, R_(T)=1.06 min.

To a solution of tert-butyl4-[(3-methoxy-3-oxopropyl)amino]piperidine-1-carboxylate (300 mg, 1.05mmol) in methanol (10 mL) was added polyformaldehyde (HCHO)n (90 mg,3.00 mmol). The reaction mixture was stirred at room temperature for 6hr, then NaBH₃CN (130 mg, 2.07 mmol) was added. The resulting solutionwas stirred at room temperature overnight and quenched with water (0.5mL). The resulting mixture was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting with 4% MeOHin DCM. This resulted in 300 mg (crude) of tert-butyl4-[(3-methoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate asyellow oil. LCMS (Method 20) [M+H]⁺=301.0, R_(T)=1.08 min.

A solution of tert-butyl4-[(3-methoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate (300mg, 1.00 mmol) and saturated HCl dioxane solution (10 mL) was stirred atroom temperature overnight. The resulting mixture was concentrated undervacuum. This resulted in 300 mg (crude) of methyl3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride as a whitesolid. LCMS (Method 20) [M+H]⁺=201.0, R_(T)=0.31 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added methyl3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (62 mg, 0.26mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The residue was passed through a short pad ofsilica gel eluting with ethyl acetate/petroleum ether (10:1). The crudeproduct was purified by Prep-HPLC with the following conditions(Prep-HPLC-005): Column, XBridge Prep C₁₈ OBD Column, 5 um, 19*150 mm;mobile phase, water with 0.05% FA and MeCN (37.0% up to 43.0% in 10 min,up to 95.0% in 1 min, hold 95.0% in 1 min, down to 37.0% in 2 min);Detector, UV 254/220 nm. This resulted in 45.2 mg (38%) of the formicacid salt of methyl3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoateas an off-white solid. LCMS (Method 24) [M+H]⁺=645.2, R_(T)=1.64 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.5, 6.9Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.55(d, 1H, J=2.7 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=4.5, 7.2 Hz),7.04 (t, 1H, J=73.2 Hz), 5.33-5.27 (m, 2H), 4.52-4.48 (m, 1H), 4.10-4.06(m, 1H), 3.66 (s, 3H), 3.51-3.34 (m, 2H), 3.16-3.08 (m, 2H), 2.86-2.51(m, 6H), 2.28-1.99 (m, 2H), 1.73-1.70 (m, 1H), 1.55-1.45 (m, 1H).

Example 346

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideformate

To a solution ofN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(130 mg, 0.29 mmol) in methanol (5 mL) was added4-(methylsulfanyl)benzaldehyde (66.3 mg, 0.44 mmol). The mixture wasstirred for 2 hr, then NaBH₃CN (27.5 mg, 0.44 mmol) was added. Theresulting solution was stirred at room temperature overnight andquenched with water (1 mL). The resulting mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 37.0%in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2min); Detector, UV 254/220 nm. This resulted in 39.6 mg (23%) of theformic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 20) [M+H]⁺=584.2, R_(T)=2.23 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6,7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.8, 8.8 Hz),7.59 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.31-7.27 (m, 3H), 7.18(d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=73.6 Hz), 4.25 (t, 2H, J=5.2 Hz), 3.70(s, 2H), 2.95-2.92 (m, 2H), 2.50 (s, 3H).

Example 347

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan-4-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol)in MeOH (20 mL) was added 5,6-dihydro-2H-pyran-2-one (530 mg, 5.40mmol). The resulting solution was stirred at room temperature for 20 h.The resulting mixture was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with 3% MeOH inDCM. This resulted in 550 mg (72%) of tert-butyl4-(2-oxooxan-4-yl)piperazine-1-carboxylate as yellow oil. LCMS (Method28) [M+H]⁺=285.0, R_(T)=0.53 min.

A mixture of tert-butyl 4-(2-oxooxan-4-yl)piperazine-1-carboxylate (550mg, 1.93 mmol) and saturated HCl dioxane solution (10 mL) was stirredovernight at room temperature. The solids were collected by filtration.This resulted in 335 mg (⁷⁸%) of 4-(piperazin-1-yl)oxan-2-onehydrochloride as a white solid.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added4-(piperazin-1-yl)oxan-2-one hydrochloride (76 mg, 0.34 mmol), DIEA(67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solutionwas stirred at room temperature overnight and concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-005): Column, XBridge Prep C₁₈ OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% FA and MeCN (35.0% up to 39.0%in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 35.0% in 2min); Detector, UV 254/220 nm. This resulted in 14.5 mg (13%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan-4-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 28) [M+H]⁺=629.1, R_(T)=1.44 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=2.0, 7.2 Hz),8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d,1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.35-4.29 (m, 1H), 4.19-4.16 (m,1H), 3.50-3.32 (m, 6H), 3.02-2.99 (m, 1H), 2.69-2.51 (m, 4H), 2.08-1.98(m, 1H), 1.77-1.75 (m, 1H).

Example 348

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.00 g,4.69 mmol) in MeOH (10 mL) was added morpholine (613 mg, 7.04 mmol). Theresulting mixture was stirred for 6 hr, then NaBH₃CN (444 mg, 7.07 mmol)was added. The resulting solution was stirred at room temperatureovernight and quenched with H₂O (1 mL). The resulting mixture wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 3% MeOH in DCM. This resultedin 1.0 g (75%) of tert-butyl 4-(morpholin-4-ylmethyl)piperidine-1-carboxylate as yellow oil. LCMS (Method 25) [M+H]⁺=285.0,R_(T)=0.59 min.

A solution of tert-butyl4-(morpholin-4-ylmethyl)piperidine-1-carboxylate (1.0 g, 3.52 mmol) andsaturated HCl dioxane solution (20 mL) was stirred at room temperatureovernight. This resulted in 660 mg (85%) of4-(piperidin-4-ylmethyl)morpholine hydrochloride as a white solid. LCMS(Method 20) [M+H]⁺=185.0, R_(T)=0.30 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.26 mmol) in DMF (2 mL) was added4-(piperidin-4-ylmethyl)morpholine hydrochloride (69 mg, 0.31 mmol),DIEA (101.2 mg, 0.78 mmol), HATU (119.2 mg, 0.31 mmol). The resultingsolution was stirred at room temperature overnight. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridgePrep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 10 mmolNH₄HCO₃ and MeCN (25.0% MeCN up to 36.0% in 10 min, up to 95.0% in 1min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220nm. This resulted in 61 mg (37%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a solid. LCMS (Method 20) [M+H]⁺=629.2, R_(T)=1.55 min. ¹H NMR (400MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d,1H, J=2.4), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.08(t, 1H, J=73.2 Hz), 5.27-5.16 (m, 2H), 4.34-4.30 (m, 1H), 3.92-3.89 (m,1H), 3.56 (t, 4H, J=4.2 Hz), 3.17-3.06 (m, 1H), 2.67-2.59 (m, 1H),2.39-2.25 (m, 4H), 2.13-2.12 (m, 2H), 1.90-1.71 (m, 3H), 1.20-1.08 (m,1H), 0.97-0.95 (m, 1H).

Example 349

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02mmol) in MeOH (50 mL) was added 1-methylpiperazine (1.0 g, 9.98 mmol)and AcOH (0.1 mL, 1.75 mmol). The reaction was stirred 3 h and NaBH₃CN(378 mg, 6.02 mmol) was added. The resulting solution was stirred atroom temperature for 12 h. The reaction was then and quenched withsaturated NH₄Cl (2 mL). The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 8% MeOH in DCM. This resulted in 800 mg (39%) of tert-butyl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate as light yellow oil.LCMS (Method 20) [M+H]⁺=284.0, R_(T)=0.97 min.

A solution of tert-butyl4-(4-methylpiperazin-1-yl)piperazine-1-carboxylate (800 mg, 1.97 mmol)and saturated HCl dioxane solution (15 mL) was stirred at roomtemperature for 3 h. The solids were collected by filtration and dried.This resulted in 600 mg (83%) of 1-methyl-4-(piperazin-1-yl)piperazinehydrochloride as a white solid. LCMS (Method 20) [M+H]⁺=184.0,R_(T)=0.32 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (200 mg, 0.35 mmol) in DMF (4 mL) was added1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (170 mg, 0.77 mmol),DIEA (134.4 mg, 1.04 mmol), HATU (160 mg, 0.42 mmol). The resultingsolution was stirred at room temperature overnight. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridgePrep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FAand MeCN (25.0% up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0%in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. Thisresulted in 74.3 mg (32%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideformate as a off-white solid. LCMS (Method 20) [M+H]⁺=628.2, R_(T)=2.20min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.36-9.34 (dd, 1H,J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4,8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H,J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.25-5.21 (m, 2H), 4.36-4.29(m, 1H), 3.98-3.79 (m, 1H), 3.10-3.00 (m, 1H), 2.69-2.51 (m, 1H),2.49-2.32 (m, 8H), 2.18 (s, 3H), 1.91-1.86 (m, 2H), 1.47-1.41 (m, 1H),1.39-1.25 (m, 1H).

Example 350

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(4-methylpiperazin-1-yl)methyl]piperidin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69mmol) and 1-methylpiperazine (703 mg, 7.02 mmol) in methanol (10 mL) wasstirred for 6 h, then NaBH₃CN (444 mg, 7.07 mmol) was added. Theresulting solution was stirred at room temperature overnight andquenched with water (1 mL). The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 5% MeOH in DCM. This resulted in 1.1 g (79%) of tert-butyl4-[(4-methylpiperazin-1-yl)methyl]piperidine-1-carboxylate as yellowoil. LCMS (Method 28) [M+H]⁺=298.0, R_(T)=0.46 min.

A mixture of tert-butyl4-[(4-methylpiperazin-1-yl)methyl]piperidine-1-carboxylate (1.1 g, 3.70mmol,) and saturated HCl dioxane solution (20 mL) was stirred at roomtemperature overnight. The solids were collected by filtration. Thisresulted in 560 mg (65%) of1-methyl-4-(piperidin-4-ylmethyl)piperazinehydrochloride as a whitesolid. LCMS (Method 20) [M+H]-=198.0, R_(T)=0.32 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (2 mL) was added1-methyl-4-(piperidin-4-ylmethyl)piperazine hydrochloride (49 mg, 0.21mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-005): Column, XBridge Prep C18OBD Column, 5 um, 19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃and MeCN (20.0% MeCN up to 30.0% in 10 min, up to 95.0% in 1 min, hold95.0% in 1 min, down to 20.0% in 2 min); Detector, UV 254/220 nm. Thisresulted in 52.7 mg (47%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(4-methylpiperazin-1-yl)methyl]piperidin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 24) [M+H]⁺=642.2, R_(T)=1.55 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.54(d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 5.26-5.16 (m, 2H), 4.37-4.30 (m, 1H), 3.93-3.87(m, 1H), 3.11-3.05 (m, 1H), 2.67-2.59 (m, 1H), 2.49-2.23 (m, 8H),2.16-2.12 (m, 5H), 1.83-1.71 (m, 3H), 1.10-1.07 (m, 1H), 0.97-0.88 (m,1H).

Example 351

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-dihydrofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.19 mmol) in DMF (3 mL) was added DIEA (48.8 mg, 0.38 mmol),4-(bromomethyl)-2,5-dihydrofuran-2-one (66.4 mg, 0.38 mmol). Theresulting solution was stirred at room temperature for 4 h andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-005): Column, XBridge Prep C18OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN(34.0% up to 39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min,down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 53.4mg (45%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-dihydrofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 24) [M+H]⁺=627.1, R_(T)=1.55 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.35 (d, 1H, J=6.8 Hz),8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d,1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.2, 7.0 Hz),7.09 (t, 1H, J=73.2 Hz), 6.12 (s, 1H), 5.25 (s, 2H), 4.91 (s, 2H), 3.51(t, 4H, J=5.4 Hz), 3.41 (s, 2H), 2.50-2.40 (m, 4H).

Example 352

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.18 mmol) in DMF (4 mL) was added DIEA (46 mg, 0.36 mmol),4-(bromomethyl)-2,5-dihydrofuran-2-one (63 mg, 0.36 mmol). The resultingsolution was stirred at room temperature overnight. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridgePrep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FAand MeCN (40.0% up to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0%in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. Thisresulted in 15.5 mg (13%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=655.2, R_(T)=1.91 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d,1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),7.09 (t, 1H, J=73.2 Hz), 6.04 (s, 1H), 5.24-5.22 (m, 2H), 4.86 (d, 2H,J=1.2 Hz), 4.39-3.37 (m, 1H), 4.01-3.93 (m, 1H), 3.47 (s, 2H), 3.10-3.01(m, 1H), 2.67-2.62 (m, 2H), 2.20 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.42(m, 1H), 1.40-1.29 (m, 1H).

Example 353

3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoicacid

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (200 mg, 0.35 mmol) in DMF (4 mL) was added ethyl3-(piperazin-1-yl)propanoate hydrochloride (90 mg, 0.40 mmol), DIEA(179.25 mg, 1.39 mmol), HATU (158.20 mg, 0.42 mmol). The resultingsolution was stirred at room temperature for 6 h. The resulting mixturewas concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 10% MeOH in DCM. This resultedin 270 mg (crude) of ethyl3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoateas a yellow solid. LCMS (Method 28) [M+H]⁺=631.2, R_(T)=0.66 min.

To a solution of ethyl3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate(270 mg, 0.43 mmol) in ethanol (10 mL) was added KOH (200 mg, 3.56 mmol)and water (4 mL). The resulting solution was stirred at room temperaturefor 1 h and neutralized with 1 N HCl solution. The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-005): Column, XBridge Prep C18OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN(27.0% up to 35.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min,down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.5mg (11%) of the formic acid salt of3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperazin-1-yl]propanoicacid as a off-white solid. LCMS (Method 28) [M+H]⁺=603.1, R_(T)=0.81min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H,J=1.4, 7.0 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8,8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H,J=4.2, 7.0 Hz), 7.08 (t, 1H, J=73.6 Hz), 5.24 (s, 1H), 3.50-3.47 (m,4H), 2.57 (t, 2H, J=7.2 Hz), 2.49-2.39 (m, 6H).

Example 354

tert-butyl(3R,4R)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylate

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine-3-carboxamide(600 mg, 1.482 mmol) in 1,2-dichloroethane (15 mL) was added Yb(OTf)₃(300 mg, 0.484 mmol), tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.20 g, 6.02 mmol). Theresulting mixture was stirred t at 65° C. overnight and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (4/1). Theregioisomeric/enantiomeric mixtures (500 mg) were separated byChiral-Prep-HPLC with the following conditions: Column, Phenomenex Lux5u Cellulose-4£

AXIA Packed 250*21.2 mm, 5 μm; mobile phase, Mobile Phase A: Hexane,Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: 35 B to 35 B in28 min; RT 1:10; RT 2:13; Detector, 254/220 nm. 30 mg product wasobtained which Alpha (25 degree C, Hex: EtOH=60:40) to give 31.3 mg(3.5%) of tert-butyl(3R,4R)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylateas a solid. (This single isomer is the first peak in Chiral-HPLC withthe above condition). LCMS (Method 20) [M+H]⁺=604.3, R_(T)=2.08 min. ¹HNMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.10 (dd, 1H, J=1.4, 6.9 Hz), 8.69-8.66(m, 2H), 8.40 (s, 1H), 7.70 (d, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=2.7, 8.7Hz), 7.40 (d, 1H, J=8.7 Hz), 7.21 (dd, 1H, J=4.2, 6.9 Hz), 6.59 (t, 1H,J=73.7 Hz), 4.37-4.03 (m, 4H), 3.03 (m, 1H), 2.15 (m, 1H), 1.59 (m, 2H),1.52 (m, 9H).

Example 355

tert-butyl (3S,4S)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylate

(This single isomer is the second peak in Chiral-HPLC with the abovecondition) to give 30.5 mg (3.5%) of tert-butyl (3S,4S)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylateas a solid. LCMS (Method 20) [M+H]⁺=604.3, R_(T)=2.08 min. ¹H NMR (300MHz, CD₃OD-d₄) δ: (ppm) 9.10 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.66 (m, 2H),8.40 (s, 1H), 7.71 (s, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.40 (d, 1H, J=8.4Hz), 7.26-7.22 (m, 1H), 6.59 (t, 1H, J=73.5 Hz), 4.37-4.03 (m, 4H), 3.03(m, 1H), 2.15 (m, 1H), 1.59 (m, 2H), 1.52 (m, 9H).

tert-butyl(3R,4R)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylate

(This single isomer is the third peak in Chiral-HPLC with the abovecondition) to give 24.8 mg (2.8%) of tert-butyl (3R,4R)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylateas a solid. LCMS (Method 20) [M+H]⁺=604.3, R_(T)=2.08 min. ¹H NMR (300MHz, CD₃OD-d₄) δ: (ppm) 9.10 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.65 (m, 2H),8.38 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H, J=7.8 Hz), 7.39 (d, 1H, J=8.7Hz), 7.25-7.22 (m, 1H), 6.83 (t, 1H, J=73.5 Hz), 4.38-4.35 (m, 1H),4.25-4.15 (m, 2H), 4.01-3.93 (m, 1H), 2.97 (m, 1H), 2.77 (m, 1H),2.17-2.13 (m, 2H), 1.53 (m, 9H).

Example 357

tert-butyl (3S,4S)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylate

(This single isomer is the fourth peak in Chiral-HPLC with the abovecondition) to give 24.9 mg (2.8%) of tert-butyl (3S,4S)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylateas a solid. LCMS (Method 20) [M+H]⁺=604.3, R_(T)=2.08 min. ¹H NMR (300MHz, CD₃OD-d₄) δ: (ppm) 9.10 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.65 (m, 2H),8.38 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.42-7.39 (d, 1H,J=8.1 Hz), 7.25-7.22 (m, 1H), 6.58 (t, 1H, J=73.5 Hz), 4.38-4.35 (m,1H), 4.25-4.15 (m, 2H), 4.01-3.93 (m, 1H), 2.97 (m, 1H), 2.77 (m, 1H),2.15-2.14 (m, 2H), 1.53 (m, 9H).

Example 358

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Assumed)

A mixture of the first peak from Example 357 chiral separation (20 mg,0.033 mmol) and saturated HCl dioxane solution (4 m) was stirred at roomtemperature for 2 h. The resulting mixture was concentrated undervacuum. This resulted in 18 mg (100%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride (assumed) as a solid. LCMS (Method 20) [M+H]⁺=504.2,R_(T)=1.38 min. ¹H NMR (300 MHz, CD₃OD-d4) δ: (ppm) 9.10 (dd, 1H, J=1.5,6.9 Hz), 8.67-8.65 (m, 2H), 8.44 (s, 1H), 7.71 (d, 1H, J=2.4 Hz), 7.56(dd, 1H, J=2.5, 8.8 Hz), 7.40 (d, 1H, J=9 Hz), 7.21 (dd, 1H, J=4.4, 7.1Hz), 6.85 (t, 1H, J=73.4 Hz), 4.45-4.43 (m, 1H), 4.28-4.23 (m, 1H),3.77-3.50 (m, 4H), 2.32-2.27 (m, 1H), 1.91-1.86 (m, 1H).

Example 359

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3 S,4S)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Assumed)

A mixture of the second peak from Example 357 chiral separation (Example358) and saturated HCl dioxane solution (4 mL) was stirred at roomtemperature for 2 h. The resulting mixture was concentrated undervacuum. This resulted in 20 mg (86%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3S,4S)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride (assumed) as a yellow solid. LCMS (Method 20)[M+H]⁺=504.2, R_(T)=1.71 min. ¹H NMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.10(d, 1H, J=6.9 Hz), 8.66-8.64 (m, 2H), 8.43 (s, 1H), 7.71 (d, 1H, J=2.7Hz), 7.55 (dd, 1H, J=2.7, 8.7 Hz), 7.39 (d, 1H, J=9.0 Hz), 7.21 (dd, 1H,J=4.1, 6.9 Hz), 6.60 (t, 1H, J=73.4 Hz), 4.47-4.44 (m, 1H), 4.28-4.21(m, 1H), 3.77-3.50 (m, 4H), 2.31-2.26 (m, 1H), 1.93-1.82 (m, 1H).

Example 360

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Assumed absolute)

A mixture of the third peak from Example 357 chiral separation (Example359) (20 mg, 0.033 mmol) and saturated HCl dioxane solution was stirredroom temperature for 2 h. The resulting mixture was concentrated undervacuum. This resulted in 11.3 mg (63%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride as a solid. LCMS (Method 20) [M+H]⁺=504.2, R_(T)=1.38 min.¹H NMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.12 (d, 1H, J=6.0 Hz), 8.73-8.66(m, 2H), 8.41 (s, 1H), 7.69 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=2.4, 8.7Hz), 7.42 (d, 1H, J=5.7 Hz), 7.23 (dd, 1H, J=4.4, 7.1 Hz), 6.62 (t, 1H,J=73.4 Hz), 4.46-4.4.28 (m, 2H), 3.69-3.61 (m, 2H), 3.26 (m, 1H),3.11-3.04 (m, 1H), 2.72-2.24 (m, 2H).

Example 361

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3 S,4S)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of fourth peak from Example 357 (Example 360) (26 mg) andsaturated HCl dioxane solution (4 mL) was stirred at room temperaturefor 2 h. The resulting mixture was concentrated under vacuum. Thisresulted in 22.4 mg (96%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3 S,4S)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride as a yellow solid. LCMS (Method 20) [M+H]⁺=504.2,R_(T)=1.73 min. ¹H NMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.08 (d, 1H, J=7.2Hz), 8.64-8.63 (m, 2H), 8.37 (s, 1H), 7.65 (d, 1H, J=2.1 Hz), 7.53 (dd,1H, J=2.1, 9.0 Hz), 7.37 (d, 1H, J=8.7 Hz), 7.19 (dd, 1H, J=4.8, 6.3Hz), 6.58 (t, 1H, J=73.5 Hz), 4.39-4.4.27 (m, 2H), 3.74-3.40 (m, 2H),3.31 (m, 1H), 3.07-3.00 (m, 1H), 2.44-2.43 (m, 2H).

ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate

To a solution ofN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(510 mg, 1.00 mmol) in EtOH (30 mL) was added, triethylamine (1.01 g,9.98 mmol) and ethyl 2-aminoacetate hydrochloride (681 mg, 4.88 mmol).The resulting solution was stirred at 80° C. for 24 h. The resultingmixture was concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 3% MeOH in DCM. This resultedin 420 mg (79%) of ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetateas light yellow oil. LCMS (Method 20) [M+H]+=534.0, R_(T)=1.18 min.

To a solution of ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate(420 mg, 0.79 mmol) in EtOH (30 mL) was added AcOH (0.1 mL, 1.75 mmol),pyridine-3-carbaldehyde (126 mg, 1.18 mmol). The mixture was stirred atroom temperature for 3 h and NaBH₃CN (99 mg, 1.58 mmol) was added. Theresulting solution was stirred at 60° C. for 12 h. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with3% MeOH in DCM. The crude product (100 mg) was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-2): Column,C₁₈ silica gel; mobile phase, CH₃CN:H₂O=5:95 increasing toCH₃CN:H₂O=24:40 within 12 min; Detector, UV 254 nm. 26 mg product wasobtained. This resulted in 25.6 mg (5%) of ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-ethyl)(pyridin-3-ylmethyl)amino]acetateas an off-white solid. LCMS (Method 20) [M+H]⁺=625.3, R_(T)=1.68 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.35 (d, 1H, J=6.8 Hz),8.69-8.68 (m, 2H), 8.39-8.37 (m, 3H), 7.63-7.61 (m, 2H), 7.51 (s, 1H),7.43 (d, 1H, J=8.8 Hz), 7.31-7.25 (m, 2H), 7.04 (t, 1H, J=73.6 Hz),4.30-4.27 (m, 2H), 4.07 (q, 2H, J=6.8 Hz), 3.82 (s, 2H), 3.44 (s, 2H),3.15-3.11 (m, 2H), 1.17 (t, 3H, J=7.2 Hz).

Example 363

2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]aceticacid

A mixture of ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate(180 mg, 0.29 mmol), ethanol (10 mL) and 1 N sodium hydroxide (2 mL) wasstirred at room temperature for 30 min. The mixture was acidified with 1HCl to pH 5. The resulting mixture was concentrated under vacuum. Thecrude product (200 mg) was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, CH3CN:H2O=5:95 increasing to CH₃CN:H₂O=24:40 within 12 min;Detector, UV 254 nm. 8.6 mg product was obtained. This resulted in 8.6mg (5%) of2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyra]zolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]aceticacid formate as a white solid. LCMS (Method 20) [M+H]⁺=597.2, R_(T)=2.72min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.72 (s, 1H), 9.34 (d, 1H, J=7.2Hz), 8.69-8.68 (m, 2H), 8.39-8.37 (m, 3H), 7.63-7.60 (m, 2H), 7.51 (d,1H, J=2.1 Hz), 7.43 (d, 1H, J=9.0 Hz), 7.32-7.22 (m, 2H), 6.99 (t, 1H,J=73.2 Hz), 4.33-4.22 (m, 2H), 3.83 (s, 2H), 3.334 (s, 2H), 3.15-3.07(m, 2H).

ethyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetate

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (665 mg, 1.44 mmol) in DMF (7 mL) was added tert-butylN-(piperidin-4-yl)carbamate (300 mg, 1.50 mmol), triethylamine (700 mg,6.92 mmol), HATU (670 g, 2.78 mol). The resulting solution was stirredat room temperature for 1.5 h. EtOAc (100 mL) and water (50 mL) wasadded. Phases were separated. The organic layer was, washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/hexane (1/1). This resulted in 600 mg (65%) of tert-butylN-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]carbamateas a yellow solid. TLC: R_(f)=0.3; ethyl acetate/petroleum ether=1/1.

TFA (2.0 mL, 26.93 mmol) was added to a solution of tert-butylN-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]carbamate(600 mg, 0.93 mmol) in dichloromethane (8 mL). The resulting solutionwas stirred room temperature for 2 h and concentrated under vacuum. Theresidue was dissolved in ethyl acetate (100 mL), and saturated NaHCO₃(50 mL) was added. Phases were separated. The organic layer was washedwith saturated NaHCO₃, brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 450 mg (89%) ofN-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. TLC: R_(f)=0.3; MeOH/DCM=1/5.

To a solution ofN-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(126 mg, 0.24 mmol) in DMF (3 mL) was added potassium carbonate (76 mg,0.55 mmol), ethyl 2-bromoacetate (0.03 mL, 0.27 mmol). The resultingmixture was stirred at 25° C. for 1 h and diluted with 100 mL of ethylacetate. Water (50 mL) was added. Phases were separated. The organicphase was washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column:Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH₄HCO₃,Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 85% B in10 min; 254 nm. This resulted in 29.3 mg (98%) of ethyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetateas a white solid. LCMS (Method 25) [M+H]⁺=631.2, R_(T)=1.89 min. ¹H NMR(400 MHz, CD₃OD-d₄) δ: (ppm) 8.98 (d, 1H, J=6.8 Hz), 8.53-8.52 (m, 2H),8.25 (s, 1H), 7.58 (d, 1H, J=2.4 Hz), 7.44 (dd, 1H, J=2.4, 8.8 Hz), 7.29(d, 1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.51 (t, 1H, J=73.6Hz), 5.20-5.13 (m, 2H), 4.32 (d, 1H, J=13.2 Hz), 4.07 (q, 2H, J=7.2 Hz),3.91 (d, 1H, J=13.2 Hz), 3.36 (s, 2H), 3.21-3.09 (m, 1H), 2.78-2.68 (m,2H), 1.94-1.83 (m, 2H), 1.34-1.22 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).

Example 365

2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]aceticacid

A mixture of ethyl2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate(200 mg, 0.32 mmol), KOH (100 mg, 1.78 mmol) in methanol (5 mL) wasstirred at 25° C. for 12 h. The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column:Xbridge C₁₈, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH₄HCO₃,Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 85% B in10 min; 254 nm. This resulted in 28.5 mg (15%) of2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidin-4-yl]amino]aceticacid as a white solid. LCMS (Method 25) [M+H]⁺=603.1, R_(T)=1.39 min. ¹HNMR (400 MHz, CD3OD-d₄) δ: (ppm) 8.98 (dd, 1H, J=1.2, 6.8 Hz), 8.54-8.53(m, 2H), 8.24 (s, 1H), 7.57 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=2.8, 8.8Hz), 7.30 (d, 1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.70 (t, 1H,J=73.4 Hz), 5.23-5.10 (m, 2H), 4.54 (d, 1H, J=13.2 Hz), 4.05 (d, 1H,J=13.6 Hz), 3.45 (s, 2H), 3.30-3.11 (m, 4H), 2.71-2.65 (m, 1H),2.11-2.05 (m, 1H), 1.58-1.43 (m, 2H).

Example 366

ethyl2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97mmol) in DCM (50 mL) was added DIEA (2.00 g, 15.47 mmol),4-dimethylaminopyridine (10 mg, 0.08 mmol) and MsCl (862 mg, 7.53 mmol).The resulting solution was stirred at room temperature for 12 h, washedwith water and brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/1). This resulted in 860 mg (62%) of tert-butyl4-(methanesulfonyloxy)piperidine-1-carboxylate as a light yellow solid.LCMS (Method 20) [M+H]⁺=224.0, R_(T)=1.42 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(500 mg, 1.24 mmol) in MeCN (50 mL) was added Cs₂CO₃ (1.21 g, 3.71mmol), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (828mg, 2.96 mmol). The resulting solution was stirred at 80° C. for 18 h.The solids were filtered out. The filtrate was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 2% MeOH in DCM. This resulted in 1.1 g (crude) oftert-butyl4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidine-1-carboxylateas a yellow solid. LCMS (Method 25) [M+H]⁺=588.0, R_(T)=1.17 min.

A mixture of crude product from previous step tert-butyl4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-piperidine-1-carboxylate(1.1 g) and saturated HCl dioxane solution (20 mL) was stirred at roomtemperature for 8 h. The resulting mixture was concentrated undervacuum. The residue was dissolved in ethanol (20 mL) and neutralizedwith 2 N NaOH to pH-8. The resulting mixture was concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with 15% MeOH in DCM. This resulted in 320 mg (35%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(320 mg, 0.66 mmol) in ethanol (20 mL) was added 50% ethyl 2-oxoacetatehydrate (268 mg, 1.31 mmol), AcOH (0.1 mL, 1.75 mmol) and NaBH₃CN (83mg, 1.32 mmol). The resulting solution was stirred at 60° C. for 12 hand concentrated under vacuum. The residue was passed through a shortpad of silica gel eluting with 2% MeOH in DCM. The crude product (100mg) was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, CH₃CN:H₂O=5:95increasing to CH₃CN:H₂O=55:75 within 12 min; Detector, UV 254 nm. 25.3mg product was obtained. This resulted in 25.3 mg (7%) of ethyl2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetateas an off-white solid. LCMS (Method 20) [M+H]⁺=574.2, R_(T)=2.70 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.36 (s, 1H), 8.69-8.67(m, 2H), 8.36 (s, 1H), 7.63-7.25 (m, 5H), 4.25-4.23 (m, 1H), 4.13-4.10(m, 2H), 3.28-3.27 (m, 2H), 3.01-2.98 (m, 2H), 2.42-2.40 (m, 2H),2.12-1.98 (m, 4H), 1.25-1.20 (m, 3H).

Example 367

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(1,3-oxazol-2-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.22 mmol) in MeOH (15 mL) was added 1,3-oxazole-2-carbaldehyde(21.7 mg, 0.22 mmol), followed by NaBH₃CN (16 mg, 0.25 mmol). Theresulting solution was stirred at room temperature for 12 h. Theresulting mixture was concentrated under vacuum. The residue was passedthrough a short pad of silica gel eluting with 5% MeOH in DCM. The crudeproduct was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBDColumn, 19&#65533;100 mm 5 um 13 nm; mobile phase, Water with 10 mMNH4CO3 and ACN (20% ACN up to 50% in 6 min); Detector, UV 254/220 nm.52.7 mg product was obtained. This resulted in 52.7 mg (45%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(1,3-oxazol-2-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 20) [M+H]⁺=529.2, R_(T)=2.42 min.¹H NMR (300 MHz, CD₃OD-d₄) δ: (ppm) 9.08 (dd, 1H, J=1.7, 7.1 Hz),8.66-8.63 (m, 2H), 8.34 (s, 1H), 7.87 (d, 1H, J=0.6 Hz), 7.67 (d, 1H,J=2.7 Hz), 7.53 (dd, 1H, J=2.4, 8.7 Hz), 7.38 (d, 1H, J=8.7 Hz), 7.19(dd, 1H, J=4.2, 7.2 Hz), 7.13 (d, 1H, J=0.6 Hz), 6.55 (t, 1H, J=73.5Hz), 4.33 (t, 2H, J=6.0 Hz), 3.95 (s, 2H), 3.14 (t, 2H, J=6.0 Hz).

Example 368

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture ofN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.29 mmol) and pyridin-3-ylmethanamine (158 mg, 1.46 mmol) inMeCN (3 mL) was stirred at 70° C. for 12 h. The resulting mixture wasconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-2): Column,C₁₈ silica gel; mobile phase, CH₃CN:H₂O=5:95 increasing toCH₃CN:H₂O=30:42 within 12 min; Detector, UV 254 nm. This resulted in57.7 mg (37%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 25) [M+H]⁺=539.1, R_(T)=0.87 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz),8.69-8.67 (m, 2H), 8.50 (d, 1H, J=1.8 Hz), 8.41 (dd, 1H, J=1.5, 4.8 Hz),8.38 (s, 1H), 7.73-7.70 (m, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.59 (d,1H, J=2.4 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.33-7.28 (m, 2H), 6.99 (t, 1H,J=73.2 Hz), 4.24 (t, 2H, J=6.0 Hz), 3.75-3.72 (m, 2H), 3.01-2.94 (m,2H), 2.27 (br, 1H).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(methylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of (2S)-2-aminopropan-1-ol (1.0 g, 13.31 mmol) in MeOH (30mL) was added, 4-methoxybenzaldehyde (1.8 g, 13.22 mmol). NaBH₃CN (600mg) was then added. The resulting solution was stirred at roomtemperature for 12 h. The solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 2.1 g (crude) of(2S)-2-[[(4-methoxyphenyl)methyl]amino]propan-1-ol as light yellow oil.LCMS (Method 27) [M+H]⁺=196.0, R_(T)=0.95 min.

To a solution of (2S)-2-[[(4-methoxyphenyl)methyl]amino]propan-1-ol (2.1g, 10.75 mmol) and 37% formaldehyde (900 mg) in methanol (50 mL) wasadded AcOH (0.1 mL, 1.75 mmol) and NaBH₃CN (1.8 g, 28.64 mmol). Theresulting solution was stirred at room temperature for 5 h, quenchedwith water (10 mL) and concentrated under vacuum. The residue wasdissolved in dichloromethane (100 mL), washed with water and brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with 10% MeOH in DCM. This resulted in 1.0 g (44%) of(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propan-1-ol as colorlessoil. LCMS (Method 21) [M+H]⁺=210.0, R_(T)=0.92 min.

MsCl (250 mg, 2.18 mmol) was added dropwise to a stirring solution of(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propan-1-ol (400 mg, 1.91mmol) and DIEA (516 mg, 3.99 mmol) in DCM (15 mL) at 0° C. The resultingsolution was stirred at room temperature for 5 h and quenched water (50mL). Phases were separated. The aqueous phase was extracted with DCM(×2) and the organic layers combined. The organic phases were washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 510 mg (crude) of[(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine as lightred oil. LCMS (Method 25) [M+H]⁺=²²⁸0.0, R_(T)=0.55 min.

A 20-mL microwave vial was charged withN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide(400 mg, 0.99 mmol), Cs₂CO₃ (652 mg, 2.00 mmol), DMF (10 mL) and[(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine (454 mg,1.99 mmol). The vessel was evacuated and refilled with nitrogen 3 times.The final reaction mixture was irradiated with microwave radiation for30 min at 120° C. The reaction was then quenched by the addition of 50mL of water. The resulting solution was extracted with dichloromethane(×2) and the organic layers combined and the organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with dichloromethane/ethyl acetate (1:1). This resulted in 420 mofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideandN-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidemixture. LCMS (Method 25) [M+H]⁺=596.0, R_(T)=0.81 min.

To the regioisomeric mixture from previous step (200 mg) in CH₃CN (20mL) was added chloro(1-chloroethoxy)methanone (240 mg, 1.68 mmol). Theresulting solution was stirred at 80° C. for 5 h. The resulting mixturewas concentrated under vacuum and dissolved with 20 mL of methanol. Theresulting solution was stirred at 80° C. for 12 h and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 5% MeOH in DCM. The crude product (120 mg) was purified byPrep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)):Column, XSelect CSH Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase,Water with 10 mmol NH4HCO3 and MeCN (26.0% MeCN up to 40.0% in 8 min);Detector, 254/220. Two fractions were obtained with the major isomer(36.3 mg) as the title compound. LCMS (Method 20) [M+H]⁺=476.2,R_(T)=2.53 min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.33(dd, 1H, J=1.2, 6.9 Hz), 8.68-8.66 (m, 2H), 8.33 (s, 1H), 7.65-7.61 (m,2H), 7.43 (d, 1H, J=7.2 Hz), 7.27 (dd, 1H, J=4.5, 7.2 Hz), 6.97 (t, 1H,J=73.5 Hz), 4.11 (dd, 1H, J=6.3, 13.5 Hz), 4.01 (dd, 1H, J=6.0, 13.5Hz), 2.97-2.91 (m, 1H), 2.29 (s, 3H), 1.76 (br, 1H), 0.95 (d, 3H, J=6.3Hz).

Example 370

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(170 mg, 0.37 mmol) in MeOH (15 mL) was added 37% formaldehyde solution(16.6 mg, 0.55 mmol), NaBH₃CN (23.3 mg, 0.37 mmol). The resultingsolution was stirred at room temperature for 12 h and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 10% MeOH in DCM. The crude product (80 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)):Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min);Detector, 254/220. This resulted in 29 mg (16%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 10) [M+H]⁺=490.1, R_(T)=0.84 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.60(d, 1H, J=2.1 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz),6.99 (t, 1H, J=73.5 Hz), 4.22 (dd, 1H, J=7.2, 13.8 Hz), 4.02 (dd, 1H,J=6.9, 13.8 Hz), 3.20-3.18 (m, 1H), 2.22 (s, 6H), 0.88 (d, 3H, J=6.6Hz).

Example 371

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(ethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.43 mmol) in EtOH (20 mL) was added acetaldehyde (48 mg, 40%aqueous solution) and NaBH₃CN (32.7 mg, 0.52 mmol). The resultingsolution was stirred at room temperature for 12 h and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 5% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLCwith the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelectCSH Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mMNH4CO3 and MeCN (26.0% MeCN up to 40.0% in 8 min); Detector, 254/220.24.2 mg product was obtained. This resulted in 24.2 mg (11%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(ethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 28) [M+H]⁺=490.1, R_(T)=0.86 min.

¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6,7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.60(dd, 1H, J=2.8, 8.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0,7.2 Hz), 7.04 (t, 1H, J=73.2 Hz), 4.11 (dd, 1H, J=6.0, 13.6 Hz), 4.01(dd, 1H, J=6.2, 13.6 Hz), 3.08-3.00 (m, 1H), 2.68-2.50 (m, 2H), 1.52(br, 1H), 0.97 (t, 3H, J=7.0 Hz), 0.95 (d, 3H, J=6.4 Hz).

Example 372

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(methylsulfanyl)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol)in DMF (30 mL) was added 1-chloro-2-(methylsulfanyl)ethane (710 mg, 6.42mmol), Cs₂CO₃ (2.6 g, 7.98 mmol). The resulting mixture was stirred at50° C. for 12 h. Water (50 mL) and EtOAc (30 mL) was added. Phases wereseparated. The aqueous phase was extracted with ethyl acetate (×2) andthe organic layers combined. The organic phases were washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1:2). This resulted in 180 mg (13%) oftert-butyl 4-[2-(methylsulfanyl)ethyl]piperazine-1-carboxylate as lightyellow oil. LCMS (Method 25) [M+H]⁺=261, R_(T)=0.63 min.

A mixture of tert-butyl 4-[2-(methylsulfanyl)ethyl]piperazine-1-carboxylate (180 mg, 0.69 mmol) in DCM (5mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for12 h. The resulting mixture was concentrated under vacuum. The residuewas dissolved in 5 mL of dioxane-HCl. The resulting mixture wasconcentrated under vacuum. This resulted in 120 mg (88%) of1-[2-(methylsulfanyl)ethyl]piperazine hydrochloride as a light yellowsolid. LCMS (Method 25) [M+H]⁺=161.1, R_(T)=0.21 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (120 mg, 0.26 mmol) in DMF (10 mL) was adde,1-[2-(methylsulfanyl)ethyl]piperazine hydrochloride (102 mg, 0.52 mmol),HATU (119 mg, 0.31 mmol), DIEA (168 mg, 1.30 mmol). The resultingsolution was stirred at room temperature for 12 h. Water (50 mL) wasadded. The resulting solution was extracted with DCM (×3) and theorganic layers combined. The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated under vacuum. Thecrude product (150 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBDColumn, 5 um, 19*150 mm; mobile phase, Water with 10 mmol NH4HCO3 andMeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resultedin 44.2 mg (28%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(methylsulfanyl)ethyl]-piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=605.2, R_(T)=1.61 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d,1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.50-3.47 (m, 4H), 2.67-2.56 (m,4H), 2.2.47-2.33 (m, 4H), 2.08 (s, 3H).

Example 373

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was added DIEA (126 mg, 0.97mmol), 1-(propan-2-yl)piperazine (126 mg, 0.98 mmol) and HATU (185 mg,0.49 mmol). The resulting solution was stirred at room temperatureovernight and concentrated under vacuum. The crude product (200 mg) waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95increasing to CH₃CN:H₂O=40:60 within 14 min; Detector, UV 254 nm. Thisresulted in 51.6 mg (28%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=573.2, R_(T)=1.80 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.9 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d,1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz),7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.52-3.48 (m, 4H), 2.78-2.65 (m,1H), 2.46-2.39 (m, 4H), 1.09-0.97 (d, 6H, J=6.6 Hz).

Example 374

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (10 mL) was added DIEA (83 mg, 0.64 mmol),1-(cyclopropylmethyl)piperazine (60.6 mg, 0.43 mmol) and HATU. Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The crude product (120 mg) was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C₁₈ silica gel; mobile phase, CH₃CN:H₂O=5:95 increasing toCH₃CN:H₂O=24:40 within 14 min; Detector, UV 254 nm. This resulted in47.6 mg (38%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=585.2, R_(T)=2.40 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d,1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz),7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.51-3.49 (m, 4H), 2.49-2.41 (m,4H), 2.23-2.21 (m, 2H), 0.87-0.82 (m, 1H), 0.50-0.44 (m, 2H), 0.13-0.08(m, 2H).

Example 375

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1l-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (500 mg,2.50 mmol) in EtOH (20 mL) was added 37% formaldehyde aqueous solution(405 mg) and AcOH (0.02 mL, 0.35 mmol).The mixture was stirred for 2hand NaBH₃CN (315 mg, 5.01 mmol) was added. The resulting solution wasstirred at room temperature overnight and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with4% MeOH in DCM. This resulted in 430 mg (80%) of tert-butyl2,4-dimethylpiperazine-1-carboxylate as colorless oil. LCMS (Method 25)[M+H]+=215.0, R_(T)=1.45 min.

A mixture of tert-butyl 2-methylpiperazine-1-carboxylate (430 mg, 2.15mmol), and saturated HCl dioxane solution (15 mL) was stirred at roomtemperature for 2 h. The resulting mixture was concentrated undervacuum. This resulted in 520 mg (crude) of 1,3-dimethylpiperazinehydrochloride as a light yellow solid. LCMS (Method 24) [M+H]⁺=115.0,R_(T)=0.25 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was added DIEA (209 mg, 1.62mmol), 1,3-dimethylpiperazine hydrochloride (146 mg, 0.97 mmol) and HATU(16 mg, 0.04 mmol). The resulting solution was stirred at roomtemperature overnight. Water (50 mL) and DCM (30 mL) was added. Phaseswere separated. The aqueous phase was extracted with DCM and the organiclayers combined. The combined organic layers were washed with brine,dried over sodium sulfate and concentrated under vacuum. The residue waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-2): Column, C18 silica gel; mobile phase, CH₃CN:H₂O=5:95increasing to CH₃CN:H₂O=24:40 within 12 min; Detector, UV 254 nm. Thisresulted in 59.1 mg (33%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LCMS (Method 25) [M+H]⁺=559.2, R_(T)=1.63 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz),8.69-8.67 (m, 2H), 8.34-8.31 (m, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55(d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz),7.02 (t, 1H, J=73.2 Hz), 5.31-5.11 (m, 2H), 4.52-4.47 (m, 0.5H),4.20-4.11 (m, 1H), 3.78-3.69 (m, 0.5H), 3.32-3.21 (m, 0.5H), 2.97-2.83(m, 0.5H), 2.75 (d, 1H, J=11.1 Hz), 2.63 (d, 1H, J=11.4 Hz), 2.20-1.71(m, 5H), 1.38-1.12 (m, 3H).

Example 376

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(3,4-dimethylpiperazin-1l-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from tert-butyl3-methylpiperazine-1-carboxylate. LCMS (Method 20) [M+H]⁺=559.2,R_(T)=2.23 min.

¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5 Hz,7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz),7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9Hz), 7.02 (t, 1H, J=73.2 Hz), 5.35-5.13 (m, 2H), 4.18-4.02 (m, 1H),3.86-3.78 (m, 1H), 3.26-3.10 (m, 1H), 2.84-2.73 (m, 2H), 2.26-1.91 (m,5H), 1.01 (d, 3H, J=6.0 Hz).

Example 377

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(2,2,4-trimethylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from tert-butyl2,2-dimethylpiperazine-1-carboxylate. LCMS (Method 25) [M+H]⁺=573.2,R_(T)=0.97 min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34(dd, 1H, J=1.2, 6.9 Hz), 8.69-8.68 (m, 2H), 8.27 (s, 1H), 7.62 (dd, 1H,J=2.7, 8.7 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28(dd, 1H, J=4.5, 6.9 Hz), 7.03 (t, 1H, 73.1 Hz), 5.17 (s, 2H), 3.48-3.42(m, 2H), 2.28-2.22 (m, 2H), 2.17 (s, 3H), 2.08 (s, 2H), 1.39 (s, 6H).

Example 378

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(3,3,4-trimethylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from tert-butyl3,3-dimethylpiperazine-1-carboxylate. LCMS (Method 20) [M+H]+=573.2,R_(T)=2.51 min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34(dd, 1H, J=1.5, 7.2 Hz), 8.69-8.67 (m, 2H), 8.33 (s, 1H), 7.62 (dd, 1H,J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28(dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.26 (s, 1H), 5.17 (s,1H), 3.51-3.48 (m, 2H), 3.22 (d, 2H, J=11.4 Hz), 2.45-2.36 (m, 2H), 2.13(s, 3H), 0.99 (s, 3H), 0.92 (s, 3H).

Example 379

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]aceticacid (100 mg, 0.22 mmol) in DMF (10 mL) was addeddimethyl[2-(piperazin-1-yl)ethyl]amine (68 mg, 0.43 mmol), DIEA (125 mg,0.97 mmol) and HATU (123 mg, 0.32 mmol). The resulting solution wasstirred at room temperature overnight and concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBDColumn, 19&#65533;100 mm 5 um 13 nm; mobile phase, Water with 10 mMNH4CO3 and ACN (15% ACN up to 40% in 6 min); Detector, UV 254/220 nm.This resulted in 79.1 mg (61%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 25) [M+H]⁺=602.2, R_(T)=0.89 min.¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7,7.1 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz),7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.48-3.42 (m, 4H), 2.45-2.32(m, 8H), 2.13 (s, 6H).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(1,3-oxazol-2-ylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol)in MeOH (15 mL) was added 1,3-oxazole-2-carbaldehyde (172 mg, 1.77mmol), AcOH (0.01 mL, 0.17 mmol), and NaBH₃CN (152 mg, 2.42 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 5% MEOH in DCM. This resultedin 480 mg (89%) of tert-butyl 4-(1,3-oxazol-2-ylmethyl)piperazine-1-carboxylate as colorless oil. TLC: R_(f)=0.4;MeOH/DCM=1/10.

A mixture of tert-butyl4-(1,3-oxazol-2-ylmethyl)piperazine-1-carboxylate (480 mg, 1.44 mmol)saturated HCl dioxane solution (15 mL) was stirred at room temperaturefor 3 h. This resulted in 300 mg (82%) of1-(1,3-oxazol-2-ylmethyl)piperazine hydrochloride as a white solid. LCMS(Method 20) [M+H]⁺=168.0, R_(T)=0.32 min.

To a solution of2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]aceticacid (100 mg, 0.22 mmol) in DMF (10 mL) was added1-(1,3-oxazol-2-ylmethyl)piperazine hydrochloride (132 mg, 0.65 mmol),HATU (123 mg, 0.32 mmol), DIEA (139 mg, 1.08 mmol). The resultingsolution was stirred at room temperature overnight. Water (50 mL) andDCM (30 mL) was added. Phases were separated. The aqueous phase wasextracted with DCM (×2) and the organic layers combined. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated undervacuum. The crude product (150 mg) was purified by Prep-HPLC with thefollowing conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridgeBEH130 Prep C18 OBD Column, 19&#65533;100 mm 5 um 13 nm; mobile phase,Water with 10 mM NH4HCO3 and ACN (28% ACN up to 38% in 6 min); Detector,UV 254/220 nm. This resulted in 68.2 mg (52%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(1,3-oxazol-2-ylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 25) [M+H]⁺=612.1, R_(T)=1.70 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 8.09 (d, 1H, J=0.6 Hz), 7.62 (dd,1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28(dd, 1H, J=4.2, 7.2 Hz), 7.18 (d, 1H, J=0.6 Hz), 7.01 (t, 1H, J=73.2Hz), 5.23 (s, 2H), 3.76 (s, 2H), 3.54-3.48 (m, 4H), 2.45-2.42 (m, 4H).

Example 381

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Methanesulfonyl chloride (2.5 g, 21.8 mmol) was added dropwise to astirring solution of tert-butyl N-(2-hydroxyethyl)carbamate (3.0 g,18.61 mmol) and DIEA (7.2 g, 55.71 mmol) in DCM (50 mL) at 0° C. Theresulting solution was stirred at room temperature for 8 h. The reactionwas then quenched by the addition of 100 mL of sodium bicarbonate.Phases were separated. The aqueous phase was extracted with DCM (×2) andthe organic layers combined. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1:2). This resulted in 3.4 g(76%) of tert-butyl N-[2-(methanesulfonyloxy)-ethyl]carbamate as a redsolid. LCMS (Method 25) [M+H]⁺=225.0, R_(T)=0.77 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.00 g, 2.47 mmol) in CH₃CN (30 mL) was added Cs₂CO₃ (2.00 g, 6.14mmol) and tert-butyl N-[2-(methanesulfonyloxy)-ethyl]carbamate (1.20 g,5.01 mmol). The resulting solution was stirred at 70° C. overnight. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith DCM/EtOAc (3:1). This resulted in 680 mg (50%) of tert-butylN-(2-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)carbamateas yellow oil. LCMS (Method 28) [M+H]⁺=548.0, R_(T)=1.33 min

A mixture of tert-butylN-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)carbamate(420 mg, 0.77 mmol) and saturated HCl dioxane solution (10 mL) wasstirred at room temperature for 3 h. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in 15 mL ofethanol. The pH value of the solution was adjusted to 8 with sodiumhydroxide (2 mol/L). The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (85/15). This resulted in 260 mg (76%) ofN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 20) [M+H]⁺=448.0, R_(T)=0.76 min.

To a solution ofN-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.45 mmol) in CH3CN (20 mL) was added (5-oxooxolan-2-yl)methyltrifluoromethanesulfonate (166 mg, 0.67 mmol) and DIEA (173 mg, 1.34mmol). The resulting solution was stirred at room temperature overnightand concentrated under vacuum. The residue was passed through a shortpad of silica gel eluting with 5% MeOH in DCM. The crude product (100mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C₁₈ OBD Column, 5um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (24.0% MeCN upto 40.0% in 8 min); Detector, 254/220. 31.6 mg product was obtained.This resulted in 32 mg (12%) of the formic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]-amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LCMS (Method 28) [M+H]⁺=546.1, R_(T)=0.82 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.64-7.62 (m, 2H), 7.44 (d, 1H,J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz),4.56-4.53 (m, 1H), 4.23 (t, 2H, J=6.4 Hz), 3.01 (t, 2H, J=6.0 Hz),2.77-2.75 (m, 2H), 2.48-2.44 (m, 2H), 2.19-2.16 (m, 1H), 1.92-1.88 (m,1H).

Example 382

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxooxolan-2-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Neat triflic anhydride Tf₂O (486 mg, 1.72 mmol) was added dropwise asolution of 5-(hydroxymethyl)oxolan-2-one (200 mg, 1.72 mmol) and DIEA(665 mg, 5.15 mmol) in DCM (20 mL) under stirring at −5° C. Theresulting solution was stirred at room temperature for 3 h and quenchedby saturated NaHCO₃ solution (50 mL). The resulting solution wasextracted with DCM (×2) and the organic layers combined. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 280 mg (crude)of (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate as a yellowliquid. TLC: R_(f)=0.5; ethyl acetate/petroleum ether=1/2.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.19 mmol) in CH₃CN (15 mL) was added DIEA (73.03 mg, 0.57mmol), and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate (93.49 mg,0.38 mmol). The resulting solution was stirred for 12 h at roomtemperature for 3 h and concentrated under vacuum. The crude product(180 mg) was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBDColumn, 19&#65533;100 mm 5 um 13 nm; mobile phase, Water with 10 mMNH4C03 and ACN (30% ACN up to 40% in 6 min); Detector, UV 254/220 nm. 65mg product was obtained. The residue was applied onto a silica gelcolumn with 5% MeOH in DCM. This resulted in 29.5 mg ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxooxolan-2-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamideas a white solid. LCMS (Method 28) [M+H]⁺=629.1, R_(T)=0.81 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d,1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz),7.02 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.71-4.66 (m, 1H), 3.50-3.33 (m,4H), 2.58 (d, 2H, J=5.4 Hz), 2.60-2.46 (m, 6H), 2.48-2.42 (m, 4H),2.30-2.21 (m, 1H), 1.90-1.83 (m, 1H).

Example 383

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]acetic acid(500 mg, 2.05 mmol) in DMF (20 mL) was added methanamine hydrochloride(406 mg, 6.01 mmol), DIEA (793 mg, 6.14 mmol) and HATU (1.17 g, 3.08mmol). The resulting solution was stirred for 12 h at room temperaturefor 12 h. Water (50 mL) was added. The resulting solution was extractedwith DCM (×3) and the organic layers combined. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 5% MeOH in DCM. This resultedin 500 mg of tert-butyl4-[(methylcarbamoyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS(Method 25) [M+H]⁺=258.0, R_(T)=0.52 min.

A mixture of tert-butyl4-[(methylcarbamoyl)methyl]piperazine-1-carboxylate (500 mg, 1.94 mmol)and saturated HCl dioxane solution was stirred at room temperature for 3h. The resulting solution was concentrated under vacuum. This resultedin 300 mg (crude) of N-methyl-2-(piperazin-1-yl)acetamide hydrochloride.LCMS (Method 20) [M+H]⁺=158.0, R_(T)=0.37 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was addedN-methyl-2-(piperazin-1-yl)acetamide hydrochloride (125 mg, 0.65 mmol),HATU (185 mg, 0.49 mmol), DIEA (126 mg, 0.97 mmol). The resultingsolution was stirred at room temperature for 12 h and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 8% MeOH in DCM. The crude product (180 mg) was purified byPrep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)):Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,Water with 10 mM NH4CO3 and MeCN (26.0% MeCN up to 40.0% in 8 min);Detector, 254/220. This resulted in 73.9 mg (38%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 20) [M+H]⁺=602.2, R_(T)=3.66 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz),8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.75 (q, 1H, J=4.8 Hz), 7.63 (dd, 1H,J=2.6, 8.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29(dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.54 (t,4H, J=5.0 Hz), 2.95 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 2.48-2.45 (m, 2H),2.44-2.41 (m, 2H).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture ofN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.20 mmol) and (1R)-1-phenylethan-1-amine (242 mg, 2.00 mmol)in MeCN (3 mL, 57.07 mmol) was stirred at 80° C. for 12 h. The crudeproduct (120 mg) was purified by Prep-HPLC with the following conditions(2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBDColumn, 19&#65533;100 mm 5 um 13 nm; mobile phase, Water with 10 mMNH4CO3 and ACN (40% ACN up to 58% in 6 min); Detector, UV 254/220 nm.This resulted in 38 mg ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a off-white solid. LCMS (Method 25) [M+H]⁺=552.1, R_(T)=1.16 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.72 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9Hz), 8.69-8.67 (m, 2H), 8.34 (s, 1H), 7.60 (dd, 1H, J=2.7, 9.0 Hz), 7.55(d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.31-7.17 (m, 6H), 6.98 (t,1H, J=73.2 Hz), 4.18 (t, 2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz),2.83-2.73 (m, 2H), 1.22 (d, 3H, J=6.6 Hz).

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1S)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from (1S)-1-phenylethan-1-amine. LCMS(Method 25) [M+H]⁺=552.1, R_(T)=1.15 min. ¹H NMR (300 MHz, DMSO-d₆) δ:(ppm) 9.72 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H),8.34 (s, 1H), 7.60 (dd, 1H, J=2.9, 8.9 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.43(d, 1H, J=8.7 Hz), 7.31-7.16 (m, 6H), 6.98 (t, 1H, J=73.2 Hz), 4.18 (t,2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m, 2H), 1.22 (d, 3H,J=6.6 Hz).

Example 386

methyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from methyl 2-aminoacetate hydrochlorideand DIEA. LCMS (Method 28) [M+H]⁺=520.1, R_(T)=0.85 min. ¹H NMR (300MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz),8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.22 (t, 2H,J=6.0 Hz), 3.62 (s, 3H), 3.37 (s, 2H), 2.98 (t, 2H, J=6.0 Hz), 2.27 (br,1H).

Example 387

methyl(2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate

To a solution of (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-hydroxybutanoic acid (2.20 g,10.03 mmol) in DCM (80 mL) was added DIEA (2.58 g, 19.96 mmol), followedby TBDMS-Cl (1.65 g, 10.95 mmol) batchwise at 0° C. The resultingsolution was stirred at room temperature for 12 h. Water (100 mL) wasadded. Phases were separated. The aqueous phase was extracted with DCM(×2) and the organic layers combined. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (4:1). This resulted in800 mg of (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyl dimethylsilyl)oxy]butanoic acid as light yellow oil. LCMS (Method 28)[M+H]⁺=275.0, R_(T)=1.16 min.

To a solution of(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyldimethylsilyl)oxy]butanoicacid (800 mg, 2.40 mmol) in DCM (30 mL) was added4-dimethylaminopyridine (29 mg, 0.24 mmol), EDC.HCl (550 mg, 2.87 mmol)and methanol (5 mL). The resulting solution was stirred at roomtemperature overnight and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1:4). This resulted in 600 mg (72%) of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyldimethylsilyl)oxy]butanoateas light yellow oil. LCMS (Method 25) [M+H]⁺=348.0, R_(T)=1.21 min.

A solution of methyl2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyldimethylsilyl)oxy]butanoate(600 mg, 1.73 mmol) in THF (2 mL), water (2 mL) and AcOH (8 mL, 139.61mmol, 80.90 equiv) was stirred at for 2 h. The reaction mixture wasneutralized with saturated sodium bicarbonate solution, extracted withDCM (×3) and the organic layers combined. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 400 mg of methyl2-[[(tert-butoxy)carbonyl]amino]-4-hydroxybutanoate as light yellow oil.LCMS (Method 28) [M+H]⁺=175, R_(T)=0.65 min.

To a stirring solution of crude methyl2-[[(tert-butoxy)carbonyl]amino]-4-hydroxybutanoate (400 mg,) in DCM (20mL) was added DIEA (387 mg, 2.99 mmol), followed by MsCl (114 mg, 1.00mmol) dropwise with stirring at 0° C. The resulting solution was stirredat room temperature for 3 h. Saturated NaHCO₃ (50 mL) was added. Theresulting solution was extracted with DCM (×2) and the organic layerscombined. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in510 mg (80%) of methyl2-[[(tert-butoxy)carbonyl]amino]-4-(methanesulfonyloxy) butanoate asyellow oil. LCMS (Method 25) [M+H]⁺=212.0, R_(T)=0.76 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.49 mmol) in CH₃CN (30 mL) wsa added Cs₂CO₃ (326 mg, 1.00mmol), and methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-(methanesulfonyloxy)butanoate(400 mg, crude). The resulting solution was stirred at room temperatureovernight. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/ethyl acetate (70/30). This resulted in280 mg (73%) of methyl2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoateas an off-white solid. LCMS (Method 25) [M+H]⁺=620.0, R_(T)=0.98 min.

The mixture of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-butanoate(280 mg), in DCM/TFA (15 mL, 2:1) was stirred at room temperatureovernight. The resulting mixture was concentrated under vacuum. Thecrude product (200 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBDColumn, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN(24.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 150 mg product wasobtained. This resulted in 148.4 mg (73%) of methyl(2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoateformate as an off-white solid. LCMS (Method 28) [M+H]⁺=520.1, R_(T)=0.82min. ¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H,J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.45(d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.01 (t, 1H, J=73.2Hz), 4.40-4.26 (m, 2H), 3.64 (s, 3H), 3.50-3.43 (m, 1H), 2.32-2.18 (m,1H), 2.11-1.99 (m, 1H).

Example 388

(1-methylpiperidin-4-yl)methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate

To a solution of 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid(1.00 g, 4.36 mmol) in DCM (50 mL) was added(1-methylpiperidin-4-yl)methanol (1.13 g, 8.75 mmol), EDC.HCl (1.0 g,5.22 mmol), 4-dimethylaminopyridine (54 mg, 0.44 mmol), The resultingsolution was stirred at room temperature overnight. Water (50 mL) wasadded. Phases were separated. The aqueous phase was extracted with DCM(×2) and the organic layers combined. The organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with 6% MeOH inDCM. This resulted in 1.2 g of 1-tert-butyl4-(1-methylpiperidin-4-yl)methyl piperidine-1,4-dicarboxylate as lightyellow oil. LCMS (Method 28) [M+H]⁺=341.0, R_(T)=0.58 min.

A mixture of 1-tert-butyl 4-(1-methylpiperidin-4-yl)methylpiperidine-1,4-dicarboxylate (1.2 g, 3.52 mmol) and saturated HCldioxane solution (15 mL) was stirred at room temperature overnight. Theresulting solution was concentrated under vacuum. This resulted in 1.5 g(crude) of (1-methylpiperidin-4-yl)methyl piperidine-4-carboxylatehydrochloride as a white solid. LCMS (Method 25) [M+H]⁺=241.0,R_(T)=0.19 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (150 mg, 0.32 mmol) in DMF (10 mL) was added(1-methylpiperidin-4-yl)methyl piperidine-4-carboxylate hydrochloride(178 mg, 0.64 mmol), DIEA (126 mg, 0.97 mmol), HATU (160 mg, 0.42 mmol).The resulting solution was stirred at room temperature overnight. Water(50 mL) was added. The resulting solution was extracted with DCM (×3)and the organic layers combined. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was passed through a short pad of silica gel elutingwith 8% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLCwith the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelectCSH Prep C₁₈ OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05%FA and MeCN (32.0% MeCN up to 50.0% in 8 min); Detector, 254/220. Thisresulted in 37 mg (16%) of the formic acid salt of(1-methylpiperidin-4-yl)methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylateas an off-white solid. LCMS (Method 25) [M+H]⁺=685.2, R_(T)=1.05 min. ¹HNMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.2, 6.8Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55(d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz),7.08 (t, 1H, J=73.2 Hz), 5.36-5.18 (m, 2H), 4.28-4.21 (m, 1H), 3.96-3.88(m, 3H), 3.25-3.12 (m, 1H), 2.86-2.74 (m, 3H), 2.73-2.66 (m, 1H), 2.15(s, 3H), 1.92-1.83 (m, 4H), 1.65-1.52 (m, 4H), 1.48-1.38 (m, 1H),1.29-1.16 (m, 2H).

Example 389

(1-methylpiperidin-4-yl)methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate

Using synthetic method anaolguous to that of(1-methylpiperidin-4-yl)methyl1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate,the title compound was prepared from1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid. LCMS(Method 28) [M+H]⁺=699.2, R_(T)=0.95 min. ¹H NMR (400 MHz, DMSO-d₆) δ:(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H),8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46(d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2Hz), 5.24 (s, 2H), 3.99-3.96 (m, 2H), 3.94-3.88 (m, 1H), 3.78-3.71 (m,1H), 3.26-3.20 (m, 1H), 3.08-3.00 (m, 1H), 2.85-2.80 (m, 2H), 2.20 (s,3H), 2.02-1.94 (m, 4H), 1.68-1.59 (m, 4H), 1.54-1.48 (m, 1H), 1.41-1.34(m, 1H), 1.28-1.23 (m, 2H), 1.18 (s, 3H).

Example 390

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in water(23 mg), followed by NaBH₃CN (24.6 mg, 0.39 mmol). The resultingsolution was stirred at room temperature for 3 h. The resulting mixturewas concentrated under vacuum. The residue was passed through a shortpad of silica gel eluting with 8% MeOH in DCM. The crude product (60 mg)was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN upto 36.0% in 8 min); Detector, 254/220. This resulted in 22.4 mg of theformic acid salt ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 28) [M+H]⁺=560.2, R_(T)=0.94 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d,1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz),7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H), 4.30-4.27 (m, 2H), 2.94-2.88(m, 2H), 2.62 (d, 2H, J=5.6 Hz), 2.44-2.41 (m, 2H), 2.32 (s, 3H),2.14-2.11 (m, 1H), 1.83-1.77 (m, 1H).

Example 391

ethyl3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoate

To a solution of tert-butyl 4-(methylamino)piperidine-1-carboxylate(1.00 g, 4.67 mmol) in ethanol (50 mL) was added AcOH (0.1 mL, 1.75mmol) and ethyl 3-oxopropanoate (1.63 g, 14.04 mmol). The mixture wasstirred at room temperature for 5 h and NaBH₃CN (882 mg, 14.04 mmol) wasadded. The resulting solution was stirred at room temperature overnightand concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with 4% MeOH in DCM. This resultedin 580 mg of tert-butyl4-[(3-ethoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate ascolorless oil. LCMS (Method 20) [M+H]⁺=315.0, R_(T)=1.14 min.

A mixture of tert-butyl4-[(3-ethoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate (580 mg,1.84 mmol) and saturated HCl dioxane solution was stirred at roomtemperature for 3 h. The resulting mixture was concentrated undervacuum. The residue was trituated with EtOAc. The solids were collectedby filtration. This resulted in 200 mg (crude) of ethyl3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride as an off-whitesolid. LCMS (Method 20) [M+H]⁺=215.0, R_(T)=0.45 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg, 0.22 mmol) in DMF (10 mL) was added HATU (123 mg, 0.32mmol), DIEA (83 mg, 0.64 mmol), and ethyl3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (200 mg). Theresulting solution was stirred at room temperature overnight. Water (50mL) was added. The resulting mixture was extracted with DCM (×3) and theorganic layers combined. The combined organic layers were washed brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product (82 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBDColumn, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN(18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. 20.3 mg productwas obtained. This resulted in 20.3 mg (13%) of the formic acid salt ofethyl3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoateas an off-white solid. LCMS (Method 28) [M+H]⁺=659.2, R_(T)=0.90 min.¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55(d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz),7.03 (t, 1H, J=73.2 Hz), 5.36-5.15 (m, 2H), 4.48-4.33 (m, 1H), 4.02 (q,2H, J=7.2 Hz), 4.00-3.96 (m, 1H), 3.18-3.00 (m, 1H), 2.89-2.80 (m, 3H),2.68-2.54 (m, 3H), 2.31 (s, 3H), 1.85-1.76 (m, 2H), 1.61-1.25 (m, 2H),1.19 (t, 3H, J=6.9 Hz).

Example 392

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of tert-butyl piperazine-1-carboxylate (1.0 g, 5.37 mmol),oxolane-2,4-dione (1.07 g, 10.69 mmol) and AcOH (0.2 mL) in THF (50 mL)was stirred at room temperature for 3 h. NaBH₃CN (508 mg, 8.08 mmol) wasadded. The resulting solution was stirred at room temperature overnight.The resulting mixture was concentrated under vacuum. The residue waspassed through a short pad of silica gel eluting withdichloromethane/ethyl acetate (1/4). This resulted in 400 mg (28%) oftert-butyl 4-(5-oxooxolan-3-yl)piperazine-1-carboxylate as light yellowoil. LCMS (Method 10) [M+H]⁺=271.0, R_(T)=0.56 min.

A mixture of tert-butyl 4-(5-oxooxolan-3-yl)piperazine-1-carboxylate(400 mg, 1.48 mmol) and saturated HCl dioxane solution (15 mL) wasstirred at room temperature for 3 h. The solids were collected byfiltration. This resulted in 380 mg (crude) of4-(piperazin-1-yl)oxolan-2-one hydrochloride as a white solid. LCMS(Method 22) [M+H]⁺=171.0, R_(T)=0.38 min.

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (200 mg, 0.43 mmol) in DMF (10 mL) was added4-(piperazin-1-yl)oxolan-2-one hydrochloride (250 mg, 1.21 mmol), HATU(247 mg, 0.65 mmol), DIEA (167 mg, 1.29 mmol)., The resulting solutionwas stirred at room temperature overnight. Water (50 mL) was added. Theresulting solution was extracted with DCM (×3) and the organic layerscombined. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspassed through a short pad of silica gel eluting with 8% MeOH in DCM.The crude product (80 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBDColumn,5 um,19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0%MeCN up to 60.0% in 10 min); Detector, 254/220. 37 mg product wasobtained. This resulted in 36.7 mg (14%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 28) [M+H]⁺=615.0, R_(T)=0.99 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9 Hz),8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 9.0 Hz), 7.56 (s,1H), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H,J=73.2 Hz), 5.24 (s, 2H), 4.44-4.38 (m, 1H), 4.26-4.18 (m, 1H), 3.49 (t,4H, J=5.1 Hz), 3.40-3.37 (m, 1H), 2.78-2.68 (m, 1H), 2.60-2.55 (m, 1H),2.47-2.35 (m, 4H).

Example 393

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (100 mg) in DMF (2 mL) was added HATU (100 mg, 0.26 mmol), DIEA (85mg, 0.66 mmol), and 4-(piperidin-4-yl)morpholine hydrochloride (67 mg,0.32 mmol). The resulting solution was stirred at room temperatureovernight. The crude product (60 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH PrepC18 OBD Column,5 um,19*150 mm; mobile phase, Water with 10 mM NH4CO3 andMeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resultedin 28.3 mg (21%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LCMS (Method 20) [M+H]⁺=615.2, R_(T)=1.84 min. ¹H NMR(300 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d,1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz),7.02 (t, 1H, J=73.2 Hz), 5.24-5.21 (m, 2H), 4.42-4.31 (m, 1H), 4.02-3.95(m, 1H), 3.55 (t, 4H, J=4.5 Hz), 3.16-3.02 (m, 1H), 2.78-2.64 (m, 1H),2.49-2.45 (m, 5H), 1.90-1.76 (m, 2H), 1.54-1.21 (m, 2H).

Example 394

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(400 mg, 0.99 mmol), (2E)-1,4-dichlorobut-2-ene (370 mg, 2.96 mmol) andcesium carbonate (1 g, 3.07 mmol) was stirred at 65° C. for 20 h. Thereaction mixture was cooled. The resulting solution was diluted withethyl acetate (100 mL), and washed H₂O (×3). The organic layer was driedover sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/hexane (1:1). The appropriate fractions were combined andconcentrated under vacuum. This resulted in 320 mg (66%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. TLC: R_(f)=0.4; ethyl acetate/petroleumether=1:1.

A solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(160 mg, 0.324 mmol) and morpholine (0.5 mL) in DMF (4 mL) was stirredat room temperature for 2 h. The resulting mixture was concentratedunder vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLCwith the following conditions (IntelFlash-1): Column, silica gel; mobilephase, CH₃CN/H₂O=20% increasing to CH₃CN/H₂O=50% within 20 min;Detector, UV 254 nm. 35.4 mg product was obtained. This resulted in 35.4mg (20%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a off-white solid. LCMS (Method 23) [M+H]⁺=544.0, R_(T)=2.37 min. ¹HNMR (400 MHz, DMSO-d₆) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.58(d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.06 (t, 1H, J=73.2 Hz), 5.94-5.84 (m, 1H), 5.79-5.69 (m, 1H), 4.82 (d,2H, J=6.0 Hz), 3.56 (t, 4H, J=4.6 Hz), 2.96 (d, 2H, J=6.4 Hz), 2.40-2.30(m, 4H).

Example 395

N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(4-methylpiperazin-1-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using synthetic method analoguous to that ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,the title compound was prepared from 1-methylpiperazine. LCMS (Method23) [M+H]⁺=557.1, R_(T)=1.76 min. ¹H NMR (400 MHz, DMSO-d₆) δ: (ppm)9.74 (s, 1H), 9.34 (d, 1H, J=5.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H),7.62 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=2.4 Hz), 7.47 (d, 1H, J=8.8 Hz),7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.92-5.80 (m,1H), 5.78-5.66 (m, 1H), 4.81 (d, 2H, J=6.0 Hz), 2.94 (d, 2H, J=6.4 Hz),2.45-2.20 (m, 8H), 2.13 (s, 3H).

Example 396

2-(methylthio)ethyl2-(2-(3-(5-chloro-2-(difluoromethoxy)phenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)ethylamino)acetate

To a solution of 2-(methylsulfanyl)ethan-1-ol (2.40 g, 26.04 mmol) inDMF (15 mL) was added 2-[(tert-butoxy)carbonyl]aminoacetic acid (3.19 g,18.21 mmol), HOBt (2.82 g, 20.87 mmol), EDC.HCl (3.99 g, 20.81 mmol) andDIEA (2 mL). The resulting solution was stirred overnight at roomtemperature. The mixture was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(3/1). This resulted in 2.00 g (31%) of 2-(methylsulfanyl)ethyl2-[[(tert-butoxy)carbonyl]amino]acetate as light yellow oil. LCMS(Method 21): [M+H]⁺=250, R_(T)=1.37 min.

To a solution of 2-(methylsulfanyl)ethyl2-[[(tert-butoxy)carbonyl]amino]acetate (2.00 g, 8.02 mmol) in dioxane(5 mL) was added saturated HCl dioxane solution (10 mL) at roomtemperature. The resulting solution was stirred at room temperature for2 h. The solids were collected by filtration. This resulted in 1.2 g of2-(methylsulfanyl)ethyl 2-aminoacetate HCl salt as a white solid. LCMS(Method 25): [M+H]⁺⁼150, R_(T)=0.28 min.

To a solution of 2-(methylsulfanyl)ethyl 2-aminoacetate HCl salt (792mg, 3.57 mmol) in CH₃CN was addedN-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(364 mg, 0.71 mmol) and DIEA (1.57 g, 12.15 mmol). The resultingsolution was stirred at 75° C. overnight and concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions conditions (2#-Waters 2767-2 (HPLC-08)): Column, Xbridge PrepPhenyl, 5 um, 19×150 mm; mobile phase, Water with 50 mmol ammoniumbicarbonate and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min,up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min);Detector, UV 220 nm. This resulted in 53.1 mg (2%) of the formic acidsalt of 2-(methylsulfanyl)ethyl2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetateas light yellow oil. LCMS (Method 20): [M+H]⁺=580.15, R_(T)=2.76 min. ¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9Hz), 8.67 (dd, 1H, J=1.5, 4.2 Hz), 8.66 (s, 1H), 8.36 (s, 1H), 7.65-7.61(m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.23 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t,1H, J=73.5 Hz), 4.27-4.18 (m, 4H), 3.38 (s, 2H), 2.99 (t, 2H, J=6.0 Hz),2.67 (t, 2H, J=6.6 Hz), 2.07 (s, 3H).

Example 397

ethyl2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate

To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg,1.92 mmol) in DMF (10 mL) was adde{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}aceticacid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). Theresulting solution was stirred at room temperature overnight andconcentrated under vacuum. The residue was purified by flashchromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg(11%) of ethyl2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetateas a white solid. LCMS (Method 20) [M+H]⁺=617.2, R_(T)=2.68 min. ¹H NMR(400 MHz, DMSO-d₆) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz),8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d,1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz),7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49(m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t,3H, J=7.2 Hz).

Example 403

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.00 g, 2.47 mmol) in N,N-dimethylformamide (10 mL), Cs₂CO₃ (970 mg,2.977 mmol) was added and stirred for 10 minutes at room temperature.Then 2-(chloromethyl)oxirane (2.28 g, 24.64 mmol) was added dropwise atroom temperature. The resulting mixture was stirred for 14 hour at roomtemperature and diluted with ethyl acetate (100 mL), washed with waterand brine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(60/40) to give 500 mg (44%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 24), [M+H]⁺'² 461.1, R_(T)=1.30min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL), DIEA (67 mg, 0.518mmol) and morpholine (14 mg, 0.161 mmol) was added at room temperature.The resulting solution was stirred at 60° C. overnight, cooled, dilutedwith 30 mL of ethyl acetate, washed with 2×10 mL of water and 2×10 mL ofbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5). This resulted in 50 mg of crude product, which was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column: XBridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/0.05% NH₄HCO₃, MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min;254 nm to obtain 40 mg (67%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-hydroxy-3-(morpholin-4-yl)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 35) [M+H]⁺=548.2, R_(T)=2.28 min. ¹H-NMR(300 MHz, DMSO-d₆): δ (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 7.2 Hz),8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.61 (s, 1H),7.44 (d, 1H, J=8.7 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H,J=73.5 Hz), 4.99 (d, 1H, J=4.5 Hz), 4.31-4.28 (m, 1H), 4.13-4.07 (m,2H), 3.56 (t, 4H, J=4.5 Hz), 2.42 (t, 4H, J=4.5 Hz), 2.32 (d, 2H, J=4.8Hz).

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxo-3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirring solution of oxalyl dichloride (0.46 mL, 0.923 mmol, 2 M)in dichloromethane (6 mL) at −78° C., a solution of DMSO (144 mg) indichloromethane (1 mL) was added dropwise in 10 min. The mixture wasstirred for an additional 10 minutes at this temperature and a solutionofN-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(253 mg, 0.461 mmol) in 2 mL of dichloromethane was added dropwise atthis temperature. The mixture was stirred for another 30 min at thistemperature. Then DIEA (476 mg, 3.683 mmol) was added dropwise at thistemperature. The resulting solution was stirred for 0.5 h at −78° C. andthen allowed warm to room temperature and stirred for another 30 min.The resulting solution was diluted with 50 mL of ethyl acetate, washedwith 2×20 mL of water and 2×20 mL of brine. The organic layer was driedover sodium sulfate and concentrated under vacuum. The crude product(200 mg) was purified by Flash-Prep-HPLC with the following conditions:Column: X Bridge RP, 19*150 mm, 5 um; Mobile Phase A:Water/0.05%NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to44% B in 10 min; 254 nm to give 108.6 mg (43%) of-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxo-3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LCMS (Method 24) [M+H]⁺=546.2, R_(T)=1.68 min. ¹H-NMR(300 MHz, CDCl₃-d): δ (ppm) 9.89 (s, 1H), 8.77 (dd, 1H, J=1.5, 6.9 Hz),8.72 (s, 1H), 8.55 (dd, 1H, J=1.5, 4.2 Hz), 8.40 (s, 1H), 7.68 (d, 1H,J=2.4 Hz), 7.42 (dd, 1H, J=2.4, 8.7 Hz), 7.28 (d, 1H, J=8.7 Hz), 6.99(dd, 1H, J=4.2, 7.2 Hz), 6.47 (t, 1H, J=73.8 Hz), 5.07 (s, 1H), 3.76 (t,4H, J=4.5 Hz), 3.26 (s, 2H), 2.56 (t, 4H, J=4.8 Hz).

Example 415

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(1-methylpiperidin-4-ylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideTo a mixture ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(215.20 mg, 0.532 mmol), Cs₂CO₃ (694.8 mg, 2.132 mmol) inN,N-dimethylformamide (15 mL) was added tert-butyl4-[2-(methanesulfonyloxy)ethylidene]piperidine-1-carboxylate (650 mg,2.128 mmol). The resulting mixture was stirred at 60° C. overnight, andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(9/1). This resulted in 310 mg (95%) of tert-butyl4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethylidene)piperidine-1-carboxylateas yellow oil. LCMS (Method 25) [M+H]=614.2, R_(T)=1.11 min.

To a solution of tert-butyl4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethylidene)piperidine-1-carboxylate(310 mg, 0.505 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (6 mL) at room temperature. The resulting solutionwas stirred for 5 h at room temperature and concentrated under vacuum.The crude product was used without further purification. LCMS (Method25) [M+H]⁺=514.1, R_(T)=0.91 min.

An aqueous solution of 40% formaldehyde (210 mg) was added to solutionofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(360.00 mg, 0.700 mmol) in methanol (30 mL). The resulting solution wasstirred at ambient temperature for 2.5 h and NaBH₃CN (44.02 mg, 0.700mmol) was added. The resulting solution was stirred at this temperaturefor 3 h and concentrated under vacuum. The residue was applied onto ashort pad of silica gel eluting with dichloromethane/MeOH (10/1). Thecrude product (60 mg) was purified by Flash-Prep-HPLC with the followingconditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/10mmolNH₄HCO₃=40% increasing to ACN/10mmolNH₄HCO₃=75% within 6 min;Detector, UV 254 nm to obtain 4.3 mg (1%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 32): [M+H]⁺=528.1, R_(T)=2.21 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6,6.8 Hz), 8.68-8.66 (m, 2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d,1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz),5.44 (t, 1H, J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H),2.52-2.50 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).

Example 421

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(2-cyanoethylamino)cyclohexylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Methanesulfonyl chloride (1.87 g, 16.325 mmol) was added dropwise to asolution of 2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethan-1-ol (2.00 g,10.86 mmol) and DIEA (4.21 g, 32.57 mmol) in dichloromethane (100 mL) atroom temperature. The resulting solution was stirred at room temperatureovernight and concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (1/9). This resulted in 1.95 g (68%) of2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl methanesulfonate asoff-white oil. TLC: R_(f)=0.6; ethyl acetate/petroleum ether=1/2.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.50 g, 3.71 mmol) in N,N-dimethylformamide (120 mL) was added Cs₂CO₃(3.62 g, 11.11 mmol) and 2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethylmethanesulfonate (1.94 g, 7.39 mmol) at room temperature. The resultingsolution was stirred for 4 h at room temperature and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (3/2) to give 1.59 g (75%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 31) [M+H]⁺=571.4, R_(T)=1.21 min.

Concentrated HCl aqueous solution (16 mL) was added to a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.59 g, 2.785 mmol) in 1,4-dioxane (160 mL). The resulting solution wasstirred at room temperature for 3 h and neutralized with saturatedsodium bicarbonate solution. The resulting mixture was concentratedunder vacuum. The residue was dissolved in dichloromethane, washed withwater, brine. The organic layer was dried, and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (3/2). This resulted in 930mg (63%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 25) [M+H]⁺=527.1, R_(T)=0.94 min.

To solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethyl]-1H-pyrazol-4-yl]pyrazoo[1,5-a]pyrimidine-3-carboxamide(300.0 mg, 0.569 mmol) in methanol (30 mL) was added3-aminopropanenitrile (199.5 mg, 2.85 mmol). The resulting solution wasstirred at room temperature for 3. Then NaBH₃CN (71.56 mg, 1.14 mmol)was added. The resulting solution was stirred at room temperatureovernight and concentrated under vacuum. The residue was applied onto ashort pad of silica gel eluting with ethyl acetate. The crude product(60 mg) was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, ACN/0.05% NH₄HCO₃=30%increasing to ACN/0.05% NH₄HCO₃=55% within 8 min; Detector, UV 254 nm.6.7 mg product was obtained. This resulted in 6.7 mg (2%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a off-white solid. LCMS (Method 34) [M+H]⁺=581.4, R_(T)=2.44 min.¹HNMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9Hz), 8.68-8.66 (m, 2H), 8.27 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d, 1H,J=8.1 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 5.45(t, 1H, J=6.9 Hz), 4.80 (d, 2H, J=7.2 Hz), 2.79-2.72 (m, 3H), 2.71-2.57(m, 5H), 2.10-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.23-1.16 (m, 2H).

Example 420

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-((2-cyanoethyl)(methyl)amino)cyclohexylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(140.0 mg, 0.241 mmol) in methanol (20 mL,) was added 40% HCHO aqueoussolution (75 mg, 0.96 mmol). The resulting solution was stirred at roomtemperature overnight. Then NaBH₃CN (15.14 mg, 0.241 mmol) was added.The resulting solution was stirred at room temperature for 4 h andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/MeOH (10/1).This resulted in 34.7 mg (24%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)(methyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 33) [M+H]⁺=595.4, R_(T)=1.43 min.¹H NMR (300 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5,6.9 Hz), 8.69-8.66 (m, 2H), 8.28 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d,1H, J=8.4 Hz), 7.27 (dd, 1H, J=4.5, 7.5 Hz), 7.00 (t, 1H, J=73.5 Hz),5.43 (t, 1H, J=7.2 Hz), 4.81 (d, 2H, J=6.9 Hz), 2.88-2.82 (m, 1H),2.66-2.59 (m, 5H), 2.33-2.29 (m, 1H), 2.22 (s, 3H), 2.10-2.05 (m, 1H),1.93-1.80 (m, 3H), 1.37-1.25 (m, 2H).

Example 452

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Sodium azide (246 mg, 2.79 mmol) was added to a solution of tert-butyl4-bromopiperidine-1-carboxylate (1.00 g, 3.79 mmol) and sodium iodide(113 mg, 0.753 mmol) in N,N-dimethylformamide (20 mL) at roomtemperature. The resulting solution was stirred at 60° C. overnight,allowed cool to cool to room temperature. Caution: the reaction shouldbe conducted behind a blast shield. The reaction was then quenched bythe addition of 10 mL of saturated sodium bicarbonate aqueous solution.The resulting solution was extracted with 2>50 mL of ethyl acetate andthe organic layers combined and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1/4). This resulted in 800 mg (93%) of tert-butyl4-azidopiperidine-1-carboxylate as colorless oil. TLC: R_(f)=0.6; ethylacetate/petroleum ether=1/4.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(2 g, 4.941 mmol) in N,N-dimethylformamide (50 mL) was added Cs₂CO₃(3.23 g, 9.913 mmo) and 3-chloroprop-1-yne (720 mg, 9.663 mmol). Theresulting mixture was stirred at 50° C. for 5 h and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate. This resulted in 1.74 g (80%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(prop-2-yn-1-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 23) [M+H]⁺=443.0R_(T)=1.45 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(prop-2-yn-1-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.68 g, 3.794 mmol) in N,N-dimethylformamide (40 mL) was added DIEA(980.6 mg, 7.587 mmol), CuI (143.7 mg, 0.755 mmol), tert-butyl4-azidopiperidine-1-carboxylate (858.8 mg, 3.795 mmol). The resultingsolution was stirred at room temperature for 7 h and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate. This resulted in 1.98 g (78%) of tert-butyl4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carboxylateas a light yellow solid. LCMS (Method 24) [M+H]⁺=669.2, R_(T)=1.34 min.

To a solution of tert-butyl4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carboxylate(1.98 g, 2.96 mmol) in methanol (30 mL) was added concentrated HClaqueous solution (15 mL). The resulting solution was stirred for 5 h atroom temperature. The resulting mixture was concentrated under vacuum.This resulted in 1.85 g crude product, which was sufficient for nextstep without further purification. A small portion was purified forcharacterization and biological submission. The crude product (100 mg)was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase,ACN/H₂O(10mmolNH₄HCO₃)=18^(%) increasing to ACN/H₂O(10mmolNH₄HCO₃)=49%within 9 min; Detector, UV 254 nm. 42.1 mg product was obtained. Thisresulted in 42.0 mg ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 36) [M+H]⁺=569.2, R_(T)=2.59 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.69 (s, 1H), 9.34 (d, 1H, J=6.4 Hz),8.68-8.64 (m, 2H), 8.40 (s, 1H), 8.22 (s, 1H), 7.67-7.61 (m, 2H), 7.45(d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.06 (t, 1H, J=73.4Hz), 5.49 (s, 2H), 4.58-4.51 (m, 1H), 3.05-3.02 (m, 2H), 2.62-2.57 (m,1H), 2.30-2.25 (br, 1H), 2.01-1.98 (m, 2H), 1.87-1.73 (m, 2H).

Example 457

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-((1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidehydrochloride (200 mg, 0.330 mmol) in dichloromethane (30 mL) was addedoxan-4-one (264.9 mg, 2.646 mmol). The resulting solution was stirred atroom temperature overnight. Then NaBH(OAc)₃ (280.8 mg, 1.325 mmol) wasadded. The resulting solution was stirred at room temperature for 6 hand concentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with DCM/MeOH (80:20). The crude product (150 mg) waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, ACN/H₂O (10 mmolNH₄HCO₃)=20% increasing to ACN/H₂O(10mmolNH₄HCO₃)=49% within 8 min;Detector, UV 254 nm. 56.9 mg product was obtained. This resulted in 56.9mg (26%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-([1-[1-(oxan-4-yl)piperidin-4-yl]-1H-1,2,3-triazol-4-yl]methyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LCMS (Method 20) [M+H]⁺=653.3, R_(T)=1.74 min.¹H NMR (400 MHz, DMSO-d₆) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6,7.2 Hz), 8.67-8.66 (m, 2H), 8.39 (s, 1H), 8.26 (s, 1H), 7.65-7.62 (m,2H), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H,J=73.4 Hz), 5.48 (s, 2H), 4.58-4.45 (m, 1H), 3.90-3.87 (m, 2H),3.32-3.25 (m, 2H), 3.04-2.98 (m, 2H), 2.51-2.33 (m, 1H), 2.30-2.24 (m,2H), 2.09-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.70-1.67 ((m, 2H), 1.49-1.40(m, 2H).

Example 468

N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopropyl)methyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.80 g, 67.1 mmol) indichloromethane (150 mL) under nitrogen was added triethylamine (11.2mL, 80.5 mmol. This was then cooled to 0° C. and to this was addeddropwise with stirring 2-chloroacetyl chloride (6.53 mL, 80.5 mmol) indichloromethane (50 mL) over 1 and a half hours. This was then stirredovernight warming to room temperature in the process. The reaction wasthen quenched by adding 1 N HCl (100 mL). This was then extracted withethyl acetate and the ethyl acetate layers were dried with solidanhydrous magnesium sulfate powder, filtered and concentrated to give2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one as a brownoil (15.44 g). This was used without purification for the next step.

ToN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(4.65 g, 11.5 mmol) and cesium carbonate (10.08 g, 30.94 mmol) was addedN,N-Dimethylformamide (40 mL) and stirred at room temperature for 5minutes. To this was added2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one (5.34 g,20.2 mmol) in N,N-Dimethylformamide (4.5 mL) and stirred at roomtemperature for 3 and a half hours. LC/MS (method 31) shows reactioncomplete. The reaction was then filtered and the filtrate wasconcentrated under reduced pressure to give a red oil. This was thendissolved in 30 mL dichloromethane and purified by ISCO using a silicacolumn and eluting with 0-100% Ethyl acetate in heptane in 5 minutesfollowed by 0-15% Methanol in dichloromethane to give 5.16 g (8.78 mmol)ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow foamy solid. LC/MS (method 39) [M+H]⁺=589.2, R_(T)=1.91 min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.01 g, 1.72 mmol) in acetone (20 mL) was added p-toluenesulfonic acid(359 mg, 2.06 mmol) and refluxed for 6 hours. LC/MS (method 31) showsproduct and presence of minor amounts of starting material. The reactionwas cooled to room temperature and quenched with water. This was thenextracted with ethyl acetate, dried with solid anhydrous magnesiumsulfate powder and fitered to give a red oil. This was then purified byISCO with a silica column and eluted with 0-15% methanol indichloromethane to afford 0.43 g (0.78 mmol) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a foamy off white solid. LC/MS (method 39) [M+H]+=544.1, R_(T)=1.91min.

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(201.7 mg 0.38 mmol) in dichloromethane (1.0 mL) was added acetic acid(0.3 mL, 5.24 mmol). To this was then added1-(aminomethyl)cyclopropanecarbonitrile (47.2 mg, 0.466 mmol). This wasthen stirred at room temperature for 5 minutes. The reaction was thencooled to 0° C. and to this was added sodium triacetyoxyborohydride(124.1 mg, 0.56 mmol) and stirred for 3 hours and let warm to roomtemperature in the process. LC/MS (method 31) shows product as a majorpeak. The reaction was quenched by adding 2 mL water followed by 10 mLsaturated sodium bicarbonate solution. This was the extracted withdichloromethane and the organic layers were dried with solid anhydrousmagnesium sulfate powder, filtered and concentrated to give a whitesolid. 20.6 mg was then purified by reverse phase HPLC purification toafford 10.2 mg ofN-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopropyl)methyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.LC/MS (method 38) [M+H]⁺=624.2, R_(T)=2.80 min. 1H NMR (400 MHz,DMSO-d6) 9.75 (s, 1H), 9.34 (dd, J=7.0, 1.7 Hz, 1H), 8.68 (dd, J=4.3,1.6 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.63 (dd, J=8.8, 2.7 Hz, 1H),7.56 (d, J=2.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.29 (dd, J=7.0, 4.2 Hz,1H), 7.25 (t, J=73.0 Hz, 1H), 5.23 (d, J=4.7 Hz, 2H), 4.12 (d, J=12.7Hz, 1H), 3.84 (d, J=13.7 Hz, 1H), 3.14 (t, J=11.9 Hz, 1H), 2.85 (t,J=11.9 Hz, 1H), 2.71-2.65 (m, 3H), 2.02 (s, 1H), 1.83 (t, J=16.2 Hz,2H), 1.33-1.12 (m, 4H), 0.94 (m, 2H).

Enzymatic Assays

JAK Enzyme Assays were Carried Out as Follows:

The activity of the isolated recombinant JAK1 and JAK2 kinase domain wasmeasured by monitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr, fluorescently labeledon the N-terminus with 5-carboxyfluorescein) using the Caliper LabChip®technology (Caliper Life Sciences, Hopkinton, Mass.). To determineinhibition constants (K_(i)), compounds were diluted serially in DMSOand added to 50 μL kinase reactions containing purified enzyme (1.5 nMJAK1, or 0.2 nM JAK2), 100 mM HEPES buffer (pH 7.2), 0.015% Brij-35, 1.5M peptide substrate, ATP (25 M), 10 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 2%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 25 μL of an EDTA containing solution (100 mM HEPES buffer(pH 7.2), 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip® 3000 according to themanufacturer's specifications. K_(i) values were then determined usingthe Morrison tight binding model (Morrison, J. F., Biochim. Biophys.Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth.Enzymol., 63:437-467 (1979)) modified for ATP-competitiveinhibition[K_(i)=K_(i,app)/(1+[ATP]/K_(m,app))].

JAK1 Pathway Assay in Cell Lines was Carried Out as Follows:

Inhibitor potency (EC₅₀) was determined in cell-based assays designed tomeasure JAK1 dependent STAT phosphorylation. As noted above, inhibitionof IL-4, IL-13, and IL-9 signaling by blocking the Jak/Stat signalingpathway can alleviate asthmatic symptoms in pre-clinical lunginflammation models (Mathew et al., 2001, J Exp Med 193(9): 1087-1096;Kudlacz et. al., 2008, Eur J. Pharmacol 582(1-3): 154-161).

In one assay approach, TF-1 human erythroleukemia cells obtained fromthe American Type Culture Collection (ATCC; Manassas, Va.) were used tomeasure JAK1-dependent STAT6 phosphorylation downstream of IL-13stimulation. Prior to use in the assays, TF-1 cells were starved ofGM-CSF overnight in OptiMEM medium (Life Technologies, Grand Island,N.Y.) supplemented with 0.5% charcoal/dextran stripped fetal bovineserum (FBS), 0.1 mM non-essential amino acids (NEAA), and 1 mM sodiumpyruvate. The assays were run in 384-well plates in serum-free OptiMEMmedium using 300,000 cells per well. In a second assay approach, BEAS-2Bhuman bronchial epithelial cells obtained from ATCC were plated at100,000 cells per well of a 96-well plate one day prior to theexperiment. The BEAS-2B assay was run in complete growth medium(bronchial epithelial basal medium plus bulletkit; Lonza; Basel,Switzerland).

Test compounds were serially diluted 1:2 in DMSO and then diluted 1:50in medium just before use. Diluted compounds were added to the cells,for a final DMSO concentration of 0.2%, and incubated for 30 min (forthe TF-1 assay) or 1 hr (for the BEAS-2B assay) at 37° C. Then, cellswere stimulated with human recombinant cytokine at their respective EC₉₀concentrations, as previously determined for each individual lot. Cellswere stimulated with IL-13 (R&D Systems, Minneapolis, Minn.) for 15 minat 37° C. The TF-1 cell reactions were stopped by the direct addition of10x lysis buffer (Cell Signaling Technologies, Danvers, Mass.), whereasthe BEAS-2B cell incubations were halted by the removal of medium andaddition of 1× lysis buffer. The resultant samples were frozen in theplates at −80 OC. Compound mediated inhibition of STAT6 phosphorylationwas measured in the cell lysates using MesoScale Discovery (MSD)technology (Gaithersburg, Md.). EC₅₀ values were determined as theconcentration of compound required for 50% inhibition of STATphosphorylation relative to that measured for the DMSO control.

Table 2 provides JAK1 K_(i), JAK2 K_(i) and IL-13-pSTAT6 IC₅₀information for the noted Examples of the indicated Tables as well asLCMS (ESI) information.

TABLE 2 IL13- IL13- LCMS LCMS pSTAT6 pSTAT6 (ESI) m/z LCMS RT JAK1 KiJAK2 Ki EC50_TF-1 EC50 Ex # [M + H]+ Method (Min) (uM) (uM) (uM)(uM)_BEAS-2B 1 488.0 5 2.93 0.00162 0.00046 0.0211 2 503.3 5 2.320.00072 0.00019 0.0052 0.0195 3 570.9 5 2.82 0.00079 0.00081 0.01670.0324 4 556.9 5 2.83 0.00066 0.00080 0.5473 5 585.0 5 2.88 0.000840.00078 0.0111 6 611.1 5 3.02 0.00071 0.00075 0.0059 7 586.0 5 2.580.00110 0.00096 1.0402 8 585.0 5 3.03 0.09634 0.11951 0.7456 9 586.0 110.90 0.00071 0.00028 0.0156 0.5543 10 571.9 11 0.90 0.00065 0.00032 11600.1 11 0.93 0.00105 0.00030 0.0118 12 599.1 5 2.96 0.00130 0.001170.0150 13 661.1 5 3.38 0.00073 0.00066 0.0220 14 615.0 5 2.86 0.001140.00113 0.3348 15 659.0 5 3.58 0.00053 0.00093 0.3345 16 647.0 5 3.240.00062 0.00056 0.0081 17 788.3 5 3.57 0.00071 0.00085 0.0809 18 682.1 52.91 0.00056 0.00056 0.2743 19 684.2 5 2.85 0.00072 0.00071 0.3792 20570.9 5 2.87 0.00051 0.00121 0.3435 21 570.9 5 2.90 0.00047 0.001163.0382 22 696.1 5 2.87 0.00094 0.00095 0.1575 23 726.2 5 3.20 0.000700.00081 0.0086 24 584.9 5 2.88 0.00078 0.00202 0.0049 25 585.0 5 2.900.00066 0.00161 0.1214 26 655.1 5 2.93 0.00077 0.00094 0.0062 27 677.0 52.84 0.00046 0.00055 0.1444 28 613.1 5 3.06 0.00082 0.00084 0.00350.1770 29 584.9 5 2.85 0.00101 0.00176 0.0056 30 584.9 5 2.85 0.000700.00169 31 663.1 5 2.84 0.00037 0.00053 0.1024 32 684.4 5 2.87 0.000460.00050 0.0985 33 689.3 5 3.29 0.00066 0.00049 0.0062 0.0485 34 732.2 53.00 0.00047 0.00046 35 766.4 5 2.94 0.00051 0.00073 0.2346 36 725.3 52.99 0.00084 0.00062 0.0576 37 677.2 5 3.26 0.00110 0.00078 0.0118 38629.2 5 2.94 0.00088 0.00078 0.0085 39 641.2 5 2.86 0.00055 0.000870.0066 40 625.2 5 3.13 0.00065 0.00061 0.0038 0.1280 41 585.2 5 2.860.00091 0.00147 0.0080 42 585.2 5 2.86 0.00069 0.00067 0.0031 43 647.2 53.24 0.00066 0.00036 0.0150 44 647.2 5 3.24 0.00054 0.00022 0.0067 45585.2 5 2.87 0.00074 0.00178 0.0071 0.0245 46 669.3 5 3.14 0.000580.00070 0.0082 47 678.3 5 3.39 0.00033 0.00054 0.0110 48 585.2 5 2.870.00094 0.00185 0.0137 0.0594 49 585.2 5 2.86 0.00050 0.00096 0.0113 50643.2 5 2.93 0.00099 0.00074 0.0320 51 728.3 5 2.99 0.00109 0.001060.0779 52 653.4 5 3.39 0.00065 0.00062 0.0054 0.0388 53 585.2 5 2.850.00061 0.00122 0.0109 54 730.4 5 3.23 0.00076 0.00067 0.0151 55 697.3 53.29 0.00085 0.00072 0.0210 56 600.1 5 2.90 0.00074 0.00026 0.0069 57626.2 5 3.07 0.00059 0.00013 0.0150 58 704.2 5 3.34 0.00060 0.000330.0256 59 639.2 5 4.10 0.00050 0.00080 0.0037 60 725.2 5 3.62 0.001100.00070 0.0462 61 585.2 5 2.91 0.00023 0.00068 0.0275 0.0324 62 585.2 52.91 0.00207 0.00268 0.0558 0.0892 63 612.2 5 2.84 0.00034 0.000700.0057 0.0122 64 545.0 5 2.81 0.00066 0.00084 65 559.0 5 2.89 0.000540.00069 0.0094 66 545.0 5 2.84 0.00058 0.00178 0.0356 0.3345 67 573.0 52.88 0.00089 0.00187 0.0146 0.0715 68 617.0 5 2.98 0.00074 0.001680.0134 69 599.1 5 2.95 0.00086 0.00245 0.0204 70 587.0 5 2.94 0.000670.00238 0.0161 71 587.0 5 3.01 0.00106 0.00466 72 587.1 5 3.01 0.001170.00407 0.0072 73 617.1 5 3.01 0.00071 0.00171 74 603.1 5 2.87 0.000970.00242 0.0385 75 587.9 11 0.91 0.00066 0.00061 0.0787 76 630.2 11 0.890.00050 0.00052 77 630.2 11 0.88 0.00060 0.00051 0.2095 78 587.9 12 1.180.00208 0.00138 0.0524 79 587.9 12 1.18 0.00454 0.00211 0.1582 80 663.25 3.26 0.00043 0.00087 0.0049 81 545.1 5 2.92 0.00535 0.00324 0.2532 82602.2 5 3.01 0.00117 0.00053 0.0087 83 559.2 5 2.84 0.00107 0.001590.0423 0.1425 84 599.2 5 3.02 0.00091 0.00147 0.0246 85 663.3 5 3.370.00086 0.00166 0.0153 0.1003 86 664.3 5 3.10 0.00072 0.00160 0.0252 87598.2 5 2.97 0.00040 0.00073 0.0154 0.0140 88 672.2 5 3.03 0.001720.00191 0.2987 89 649.2 5 3.38 0.00088 0.00145 0.0227 90 679.3 5 3.120.00095 0.00131 0.0233 91 665.2 5 3.10 0.00075 0.00115 0.1487 92 683.2 53.50 0.00092 0.00203 0.0556 93 717.3 5 3.63 0.00128 0.00258 0.0959 94697.3 5 3.57 0.00120 0.00207 0.0424 0.0931 95 693.3 5 3.38 0.000800.00260 0.0173 96 643.3 5 2.90 0.00063 0.00140 0.0041 97 731.3 5 3.700.00116 0.00197 0.1869 98 649.3 5 3.22 0.00079 0.00181 0.0038 0.0381 99641.2 5 4.39 0.00040 0.00076 0.0017 0.0305 100 679.3 5 3.35 0.000840.00201 0.0054 101 669.3 5 3.63 0.00067 0.00177 0.0165 102 699.2 5 3.710.00062 0.00110 0.0085 0.0347 103 731.3 5 5.49 0.00398 0.00795 0.2649104 757.2 5 3.65 0.00093 0.00211 0.0202 105 757.2 5 3.52 0.00145 0.003170.0500 106 713.3 5 3.48 0.00109 0.00229 0.0155 107 713.2 5 3.55 0.000970.00249 0.0176 108 735.4 5 3.81 0.00247 0.00366 0.0431 109 719.5 5 3.640.00322 0.00730 0.0429 110 693.5 5 3.51 0.00104 0.00203 0.0089 0.0875111 739.4 5 4.00 0.00310 0.01061 0.2030 112 693.4 5 3.38 0.00045 0.001010.0963 113 741.4 5 3.74 0.00119 0.00215 0.0306 114 680.4 5 3.43 0.000520.00134 0.0153 115 683.3 5 5.43 0.00128 0.00248 0.0577 116 717.3 5 5.380.00376 0.00704 0.0233 117 725.4 5 3.97 0.00051 0.00113 0.0086 0.0546118 731.4 5 4.01 0.00257 0.00445 0.1001 0.3030 119 727.2 5 3.45 0.001210.00051 0.0208 120 705.4 5 3.78 0.00030 0.00023 0.1179 121 717.3 5 3.560.00024 0.00031 0.1397 122 727.3 5 3.43 0.00027 0.00017 0.0249 123 677.35 3.49 0.00223 0.00163 0.0076 0.0487 124 691.3 5 3.48 0.00121 0.002900.0879 0.5355 125 707.4 5 3.55 0.00061 0.00220 0.0117 126 683.3 5 3.400.00063 0.00180 0.0149 127 721.4 5 3.80 0.00078 0.00244 0.0724 128 717.35 3.51 0.00112 0.00309 0.0425 129 677.3 5 3.46 0.00114 0.00333 0.0142130 699.3 5 3.50 0.00110 0.00291 0.0323 131 745.3 5 3.46 0.00107 0.002680.0237 132 703.3 5 4.87 0.00057 0.00127 0.0031 0.0973 133 731.3 5 5.560.00651 0.00833 134 637.2 5 3.09 0.00033 0.00069 0.0023 0.0118 135 681.35 3.32 0.00052 0.00115 0.0269 136 574.0 12 1.18 0.00064 0.00025 0.0367137 632.0 11 0.94 0.00053 0.00072 138 560.2 11 0.87 0.00052 0.00026 139588.2 5 2.93 0.00078 0.00036 0.0402 140 617.9 11 0.88 0.00046 0.000390.0293 141 632.1 11 0.90 0.00068 0.00059 0.0150 142 587.0 5 2.91 0.001650.00038 0.0363 143 656.1 5 3.47 0.00076 0.00018 0.0204 144 628.0 7 0.980.00054 0.00017 0.0128 0.0213 145 664.0 9 1.26 0.00057 0.00016 0.0148146 628.0 9 1.20 0.00045 0.00013 0.0039 147 658.0 9 1.19 0.00055 0.000140.0118 148 616.0 11 0.99 0.00064 0.00010 0.0094 149 601.9 13 1.750.00081 0.00020 0.0083 0.0198 150 602.0 11 0.98 0.00073 0.00017 0.0201151 678.0 11 1.04 0.00200 0.00042 0.0938 152 657.3 5 3.03 0.001080.00019 0.0119 153 629.2 5 2.91 0.00155 0.00027 0.0365 154 628.3 5 3.060.00142 0.00023 0.0027 155 613.2 5 3.01 0.00156 0.00024 0.0051 156 601.25 3.05 0.00153 0.00019 0.0318 157 559.1 5 2.93 0.00132 0.00075 0.0092158 615.3 5 2.47 0.00212 0.00026 0.0388 159 631.2 5 2.53 0.00232 0.000240.0578 160 573.3 5 2.90 0.00302 0.00039 0.0193 161 663.3 5 2.92 0.001230.00013 0.0223 162 588.1 5 2.93 0.00059 0.00018 0.0154 163 629.1 5 2.990.00069 0.00019 0.0073 164 643.1 5 3.13 0.00044 0.00006 0.0056 165 574.25 2.88 0.00038 0.00015 0.0069 166 719.4 5 3.60 0.00091 0.00026 0.0229167 678.3 5 3.49 0.00053 0.00018 0.0197 168 587.3 5 3.03 0.00147 0.000290.0077 169 643.2 5 3.03 0.00116 0.00022 0.0068 170 573.3 5 2.86 0.001670.00025 0.0114 171 516.9 11 0.98 0.00072 0.00017 0.0219 172 530.9 110.99 0.00088 0.00015 0.0159 173 642.3 5 3.00 0.00058 0.00013 0.0048 174559.1 5 3.27 0.00067 0.00009 0.0123 175 617.2 5 3.32 0.00078 0.000130.0134 176 561.2 5 2.96 0.00068 0.00012 0.0127 177 623.2 5 3.02 0.000450.00009 0.0150 178 593.2 5 3.43 0.00123 0.00043 0.0839 179 635.2 5 3.790.00304 0.00090 0.1302 180 637.3 5 3.65 0.00125 0.00035 0.0384 181 679.35 3.79 0.00199 0.00048 0.0956 182 502.9 12 1.23 0.00049 0.00020 0.0089183 502.9 11 1.00 0.00049 0.00023 0.0068 184 547.3 11 1.00 0.000760.00018 0.0035 185 489.1 11 0.91 0.00059 0.00031 186 488.9 12 1.100.00071 0.00020 0.0123 187 742.4 5 3.94 0.00705 0.00903 188 548.1 5 3.200.00126 0.00084 0.0058 0.0349 189 587.2 5 3.19 0.00259 0.00161 0.00530.0200 190 562.1 5 3.18 0.00269 0.00202 0.0146 0.0098 191 576.1 5 3.290.00293 0.00292 0.0105 192 638.2 5 3.73 0.00500 0.00372 0.2723 193 619.15 3.03 0.00223 0.00146 0.0235 194 578.2 5 3.15 0.00228 0.00144 0.0174195 560.1 5 3.07 0.00136 0.00086 0.0165 196 596.1 5 3.71 0.00174 0.001050.0174 197 586.3 5 3.10 0.00089 0.00086 0.0062 198 616.1 5 5.36 0.002720.00217 0.0291 199 590.3 5 3.51 0.00122 0.00107 0.0073 200 618.2 5 3.170.00124 0.00107 0.0059 0.0254 201 624.2 5 3.55 0.00505 0.00376 0.1837202 727.4 5 4.89 0.00110 0.00182 0.0158 203 655.3 5 3.96 0.00548 0.00415204 766.4 5 3.77 0.00200 0.00141 0.0079 0.1715 205 520.2 5 3.02 0.000800.00058 0.0044 0.0338 206 610.2 5 3.64 0.01404 0.00867 207 560.1 5 3.260.00101 0.00069 0.0236 208 588.0 5 5.29 0.00138 0.00108 0.0335 209 503.05 3.16 0.00078 0.00028 0.0074 0.0415 210 545.1 5 3.48 0.00016 0.000100.2397 211 570.9 5 2.86 0.00110 0.00138 0.0209 212 585.1 5 2.92 0.000910.00193 0.0306 213 615.2 5 2.97 0.00149 0.00234 214 556.9 5 2.82 0.001170.00129 215 630.2 12 1.12 0.00133 0.00126 216 585.0 5 2.87 0.001130.00182 0.0125 217 570.9 5 2.87 0.00107 0.00137 218 585.0 5 2.92 0.001010.00308 0.0756 219 556.9 5 2.87 0.00056 0.00128 1.0320 220 556.9 5 2.840.00122 0.00271 1.1706 221 570.9 5 2.88 0.00092 0.00168 0.1305 222 599.05 2.94 0.00054 0.00159 0.0289 223 584.9 5 2.94 0.00044 0.00072 0.1867224 599.0 5 2.96 0.00056 0.00147 0.0193 225 641.3 5 3.15 0.00039 0.001290.0050 0.0423 226 816.4 5 3.59 0.00041 0.00111 0.0415 227 545.1 5 2.890.00055 0.00093 0.0036 0.0271 228 575.1 5 2.84 0.00047 0.00089 0.01110.0655 229 589.1 5 2.98 0.00038 0.00084 0.0033 0.0516 230 589.1 5 2.840.00061 0.00071 231 619.2 5 2.85 0.00054 0.00118 232 637.1 5 3.050.00074 0.00146 233 559.1 5 2.89 0.00078 0.00143 0.0100 0.0181 234 575.05 2.83 0.00058 0.00122 235 575.1 5 2.82 0.00058 0.00108 0.0213 0.1140236 607.0 5 4.68 0.00041 0.00074 237 632.1 5 4.47 0.00032 0.00076 238646.1 5 3.32 0.00045 0.00055 0.0218 239 559.1 5 2.87 0.00155 0.002380.0086 240 589.1 5 2.88 0.00100 0.00168 241 585.1 5 2.98 0.00087 0.00125242 571.0 5 2.89 0.00095 0.00103 243 560.0 5 2.88 0.00049 0.00036 244589.9 11 0.90 0.00049 0.00024 245 604.0 11 0.94 0.00035 0.00022 246573.9 11 0.91 0.00108 0.00057 0.0488 247 574.1 11 0.91 0.00055 0.00030248 600.2 11 0.94 0.00062 0.00039 249 545.9 12 1.09 0.00073 0.000440.0323 250 572.0 11 0.89 0.00139 0.00048 251 574.0 11 1.01 0.000830.00046 252 571.9 11 0.99 0.00081 0.00015 0.0430 253 652.3 5 3.350.00056 0.00041 0.0183 254 499.0 5 3.87 0.00163 0.00077 0.1174 255 555.15 3.39 0.00056 0.00040 0.0862 256 585.2 5 3.45 0.00131 0.00095 0.0920257 603.1 5 4.28 0.00293 0.00210 1.0000 258 596.1 5 3.46 0.00117 0.000720.0710 259 624.2 5 3.29 0.00093 0.00056 0.0130 260 562.1 5 2.56 0.007740.00265 0.0685 261 569.1 5 3.62 0.01790 0.01024 262 560.1 5 2.85 0.005840.00173 0.0627 263 519.0 5 3.23 0.00150 0.00203 0.0192 264 574.1 5 3.060.00269 0.00238 0.0198 265 576.1 5 3.09 0.00363 0.00429 0.0228 266 575.25 3.64 0.00024 0.00010 0.0059 267 576.1 5 3.50 0.00066 0.00062 0.0358268 546.1 5 3.68 0.00049 0.00046 0.0055 269 545.9 5 3.55 0.00033 0.00083270 547.0 11 1.01 0.00024 0.00020 271 517.2 11 1.06 0.00021 0.00013 272576.0 5 3.30 0.00033 0.00078 273 577.1 12 1.17 0.00049 0.00023 274 560.05 3.58 0.00034 0.00091 0.0032 0.0131 275 590.1 5 3.54 0.00031 0.00089276 623.1 5 3.05 0.00023 0.00018 277 562.0 5 3.43 0.00051 0.00083 278546.0 5 3.51 0.00024 0.00063 0.0050 279 651.2 12 1.35 0.00039 0.00022280 560.0 5 3.69 0.00039 0.00081 0.0043 0.0215 281 631.0 5 4.75 0.000480.00045 0.0022 282 567.0 11 1.10 0.00017 0.00012 283 646.1 11 1.190.00055 0.00029 284 528.0 5 4.28 0.00015 0.00037 0.0016 0.0125 285 637.111 1.20 0.00061 0.00047 286 637.0 11 1.23 0.00054 0.00026 287 552.0 54.22 0.00035 0.00065 288 532.0 5 3.77 0.00058 0.00111 0.0028 0.0363 289622.0 5 4.22 0.00030 0.00038 290 547.0 11 1.04 0.00024 0.00011 291 546.05 3.69 0.00054 0.00055 0.0036 0.0317 292 503.0 5 4.52 0.00039 0.000400.0014 0.0210 293 546.0 5 3.83 0.00029 0.00038 0.0030 0.0081 294 506.0 53.00 0.00089 0.00057 0.0062 0.0367 295 463.0 5 2.81 0.00049 0.000210.0055 0.0345 296 531.2 5 3.10 0.00026 0.00021 0.0056 0.0283 297 489.1 52.87 0.00032 0.00007 0.0071 0.0308 298 503.2 5 2.93 0.00052 0.000180.0044 0.0215 299 595.2 5 3.08 0.00038 0.00039 0.0041 0.0104 300 615.0 54.42 0.00028 0.00018 0.0040 0.0142 301 581.2 5 3.22 0.00033 0.000360.0034 0.0095 302 635.2 5 3.27 0.00060 0.00111 0.0162 303 703.3 5 5.090.00190 0.00328 0.0784 304 475.1 17 6.52 0.00078 0.00039 0.0059 0.0469305 489.1 18 7.75 0.00061 0.00032 0.0109 0.0426 306 534.2 14 1.130.00115 0.00054 0.0062 0.0659 307 574.2 15 2.23 0.00145 0.00059 0.00610.0250 308 530.1 5 4.27 0.00024 0.00055 0.0015 0.0236 309 534.1 16 2.680.00134 0.00047 0.0163 0.0490 310 589.2 26 0.82 0.00052 0.00059 8.8300311 589.1 25 0.85 0.00125 0.00073 2.6000 312 522.2 20 2.5 0.000400.00032 0.0719 313 538.2 20 2.7 0.00021 0.00021 0.0218 314 539.2 20 2.530.00062 0.00039 0.0995 315 539.1 25 1.45 0.00072 0.00040 0.0823 316 63521 1.56 0.00048 0.00104 0.1420 317 587.1 25 1.8 0.00064 0.00116 0.0229318 615.2 25 0.93 0.00056 0.00111 0.0283 319 573.2 20 2.86 0.000500.00086 0.0577 320 621 21 1.53 0.00031 0.00060 0.0473 321 644.2 20 2.340.00040 0.00090 0.0133 322 603.2 20 2.83 0.00031 0.00080 0.0411 323503.1 20 1.65 0.00068 0.00033 0.0209 324 531.2 20 2.67 0.00095 0.001610.0566 325 616.3 20 2.41 0.00041 0.00103 0.0651 326 554.2 20 2.790.00021 0.00028 0.0070 327 554.2 20 1.58 0.00025 0.00020 0.0077 328554.2 20 1.58 0.00021 0.00023 0.0102 329 617.2 24 1.53 0.00030 0.000760.0115 330 643.2 25 1.49 0.00039 0.00088 0.0343 331 617.1 25 1.510.00039 0.00077 0.0176 332 631.2 28 0.89 0.00049 0.00091 0.0692 333700.2 24 2.21 0.00069 0.00196 0.0065 334 714.2 24 2.42 0.00069 0.001810.0061 335 714.2 24 1.94 0.00084 0.00222 0.0121 336 687.2 28 0.860.00049 0.00105 0.0145 337 728.2 24 1.87 0.00083 0.00252 0.0232 338645.2 24 2.97 0.00036 0.00116 0.0177 339 701.2 20 0.92 0.00041 0.001010.0094 340 659.2 28 1.23 0.00044 0.00179 0.0090 341 671.3 20 1.580.00053 0.00262 0.5340 342 574.1 28 1.11 0.00019 0.00020 1.8100 343588.2 20 2.79 344 657.2 24 1.68 0.00070 0.00190 0.0484 345 645.2 24 1.640.00059 0.00147 0.0166 346 584.2 20 2.23 0.00037 0.00031 0.1150 347629.1 28 1.44 0.00039 0.00076 0.0307 348 629.2 20 1.55 0.00040 0.001020.0120 349 628.2 20 2.2 0.00055 0.00165 0.0155 350 642.2 24 1.55 0.000430.00142 0.0094 351 627.1 24 1.55 0.00046 0.00094 0.0365 352 655.2 201.91 0.00033 0.00075 0.0124 353 603.1 28 0.81 0.00032 0.00036 3.6100 354604.3 20 2.08 0.00072 0.00105 0.0240 355 604.3 20 2.08 0.00332 0.003720.0678 356 604.3 20 2.08 0.00264 0.00237 0.0396 357 604.3 20 2.080.00122 0.00106 0.0216 358 504.2 20 1.38 0.00093 0.00066 0.0133 359504.2 20 1.71 0.00385 0.00270 0.0309 360 504.2 20 1.38 0.00469 0.001700.0366 361 504.2 20 1.71 0.00294 0.00205 0.0273 362 625.3 20 1.680.00504 0.00327 363 597.2 20 2.72 0.00415 0.00121 3.7800 364 631.2 251.89 0.00077 0.00160 0.0952 365 603.1 25 1.39 0.00041 0.00055 7.5600 366574.2 20 2.7 0.00107 0.00099 0.3120 367 529.2 20 2.42 0.00083 0.000500.0352 368 539.1 25 0.87 0.00072 0.00051 0.0560 369 476.2 20 2.530.00113 0.00125 0.0093 370 490.1 28 0.84 0.00137 0.00137 0.0402 371490.1 28 0.86 0.00114 0.00119 0.0146 372 605.2 20 1.61 0.00025 0.000510.0197 373 573.2 20 1.8 0.00070 0.00124 0.0342 374 585.2 20 2.4 0.000450.00088 0.0295 375 559.2 25 1.63 0.00075 0.00154 0.0716 376 559.2 202.23 0.00066 0.00103 0.0325 377 573.2 25 0.97 0.00056 0.00130 0.0528 378573.2 20 2.51 0.00093 0.00160 0.0874 379 602.2 25 0.89 0.00086 0.002330.0755 380 612.1 25 1.7 0.00030 0.00068 0.0481 381 546.1 28 0.82 0.001070.00055 0.0298 382 629.1 28 0.81 0.00034 0.00075 0.0257 383 602.2 203.66 0.00039 0.00066 0.2770 384 552.1 25 1.16 0.00030 0.00023 0.1390 385552.1 25 1.15 0.00045 0.00030 0.1630 386 520.1 28 0.85 0.00106 0.000560.0297 387 520.1 28 0.82 0.00124 0.00046 0.0107 388 685.2 25 1.050.00051 0.00242 0.0241 389 699.2 28 0.95 0.00040 0.00216 0.0175 390560.2 28 0.94 0.00128 0.00084 0.0424 391 659.2 28 0.9 0.00091 0.002490.0206 392 615 28 0.99 0.00040 0.00077 0.0261 393 615.2 20 1.84 0.000380.00089 0.0115 394 544 23 2.37 0.00087 0.00061 0.0311 395 557.1 23 1.760.00129 0.00096 0.0224 396 580.1 20 2.76 0.00329 0.00129 0.0382 397617.2 20 2.68 0.00028 0.00077 0.0270 398 656.4 20 1.45 0.00050 0.001450.0183 399 518.1 23 1.46 0.00090 0.00039 0.0232 400 644.3 20 2.380.00058 0.00173 0.0309 401 630.2 20 2.34 0.00075 0.00203 0.1520 402518.2 20 1.45 0.00083 0.00040 0.0187 403 548.2 35 2.28 0.00146 0.000710.0283 404 506.1 24 2.41 0.00168 0.00061 0.0078 405 546.2 24 1.960.00173 0.00068 0.0257 406 584.3 20 2.32 0.00046 0.00099 0.0333 407628.3 20 1.41 0.00036 0.00071 0.1720 408 642.2 30 0.93 0.00059 0.002290.1210 409 624.1 32 1.65 0.00036 0.00089 0.0196 410 629.3 20 1.460.00060 0.00125 0.0183 411 504.2 24 2.57 0.00170 0.00043 0.0228 412546.2 24 1.68 0.00170 0.00096 0.0395 413 626.4 33 1.24 0.00025 0.000740.0209 414 638.3 29 1.56 0.00030 0.00076 0.0182 415 528.1 32 2.210.00299 0.00209 0.0460 416 642.5 31 1.35 0.00041 0.00084 0.0316 417531.2 35 2.3 0.00291 0.00137 0.0934 418 544.2 24 2.36 0.00243 0.000800.0609 419 612.4 33 1.23 0.00041 0.00106 0.0313 420 595.4 33 1.430.00057 0.00081 0.0301 421 581.4 34 2.44 0.00065 0.00089 0.0498 422528.2 20 1.59 0.00089 0.00177 0.0610 423 684.4 19 1.86 0.00073 0.002790.0312 424 670.3 20 1.5 0.00112 0.00344 0.0987 425 670.4 20 2.51 0.000600.00164 0.0411 426 656.3 20 1.46 0.00053 0.00125 0.0394 427 713.3 250.95 0.00042 0.00125 0.0224 428 713.3 25 0.9 0.00079 0.00251 0.0453 429615.2 20 1.45 0.00048 0.00099 0.0074 430 571.2 25 1.11 0.00051 0.000770.0058 431 624.2 24 1.76 0.00029 0.00074 0.0029 432 629.2 20 2.680.00040 0.00120 0.0326 433 645.2 24 1.58 0.00042 0.00116 0.0360 434631.2 20 1.52 0.00031 0.00067 0.0187 435 652.2 24 2.9 0.00034 0.000980.0074 436 610.1 24 2.73 0.00025 0.00075 0.0103 437 601.2 24 1.460.00038 0.00088 0.0126 438 659.1 25 1.06 0.00059 0.00192 0.0150 439571.2 20 1.49 0.00071 0.00078 0.0353 440 585.2 24 1.59 0.00046 0.000540.0068 441 629.4 20 2.54 0.00052 0.00148 0.0084 442 629.2 20 2.680.00033 0.00084 0.0194 443 647.1 24 1.34 0.00023 0.00063 0.0663 444557.2 20 1.45 0.00076 0.00089 0.0540 445 628.4 20 1.43 0.00035 0.000870.3000 446 610.3 20 2.46 0.00045 0.00130 0.0121 447 627.2 25 0.960.00049 0.00125 0.0161 448 642.2 24 1.43 0.00036 0.00088 0.0425 449629.3 20 1.46 0.00038 0.00110 0.0136 450 627.2 25 0.97 0.00037 0.000970.0126 451 629.3 20 2.29 0.00045 0.00156 0.0201 452 569.2 36 2.590.00071 0.00065 0.0809 453 673.3 25 1.14 0.00041 0.00130 0.0304 454583.2 24 1.58 0.00040 0.00023 0.0235 455 639.2 24 2.47 0.00030 0.000150.0210 456 612.2 20 1.49 0.00049 0.00111 0.0410 457 653.3 20 1.740.00045 0.00026 0.0156 458 629.2 20 2.53 0.00047 0.00090 0.0081 459615.2 20 1.46 0.00030 0.00072 0.0075 460 660.2 24 1.63 0.00039 0.001100.0068 461 598.2 20 2.34 0.00040 0.00084 0.0117 462 638.1 23 2.550.00038 0.00086 0.0108 463 623.1 25 1.28 0.00031 0.00070 0.0070 464626.3 20 2.41 0.00049 0.00141 0.0095 465 640.2 25 2.94 0.00024 0.000560.0114 466 626.2 24 1.85 0.00027 0.00074 0.0140 467 639.2 37 3.150.00024 0.00064 0.0075 468 624.2 38 2.8 0.00036 0.00092 0.0060 Blank:Not determined

Clearance Assay

In certain instances high systemic clearance of a drug substance may beof benefit. For example, in the treatment of pulmonary diseases it maybe beneficial to have high drug concentrations in the lung, with lowerconcentrations in the bloodstream or peripheral organs. In such cases,it may be advantageous to administer a drug substance with high systemicclearance via the inhaled delivery route. This approach may maximizepharmacologic activity of the drug substance in the lung whileminimizing the possibility of on-target toxicity elsewhere in the body.The functional groups appended to the 5-chloro-2-difluoromethoxyphenylpyrazolopyrimidine scaffold affect systemic clearance. For example,compound i exhibits a mouse intravenous (IV) clearance value of 5.3mL/min/kg, or 6% of mouse liver blood flow. Representative mouse IVclearance values for examples in the present invention are shown inTable 3.

TABLE 3 Mouse IV clearance values for compounds in the presentinvention. IV Mouse CL, IV Mouse CL, % Ex # mL/min/kg of liver bloodflow 2 580 >100% 3 216 >100% 59 39 43% 63 139 >100% 67 205 >100% 85 5561% 98 178 >100% 99 234 >100% 102 140 >100% 134 222 >100% 198 326 >100%205 46 51% 209 64 71% 233 153 >100% 278 133 >100% 284 219 >100% 29495 >100% 313 51 57% 338 >200 >100% 348 143 >100% 372 93 >100% 397141 >100% 466 72 80% 468 140 >100%

Female BALB/c mice were obtained from Charles River Labs (Hollister,Calif. USA). Twelve animals were given a single IV dose of 1 mg/kg ofcompounds via the tail vein. A representative dose solution was preparedas follows: the compound was dissolved in a mixture of 5%dimethylsulfoxide (DMSO), 35% polyethylene glycol (PEG 400), and 60%water (v/v/v), respectively, and administered at a dosing volume of 5mL/kg. Mice weighed approximately 20-25 g at the start of the study.After intravenous administration of compounds, each animal was bledtwice via retro-orbital and cardiac puncture. PK time points werecollected at 2 min, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hrpost-dose. Plasma samples were stored at approximately −80° C. untilthawed for LC-MS/MS analysis. PK data analysis was performed on meanplasma concentration-time data and PK parameters were determined by noncompartmental methods using WinNonlin® Enterprise, version 5.2.1(Pharsight Corporation; Mountain View, Calif.).

What is claimed is:
 1. A compound of Formula (00A):

and stereoisomers and salts thereof, wherein: R⁰⁰ is H or CH₃; R⁰¹ is Hor NH₂; R⁰ is H or NH₂; and Ring Q is either (i) or (ii):

wherein: t¹ and t² are each independently 0 or 1; X^(A) and X^(B) areindependently selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₄ alkenyl, —NR^(a)R^(b), C₂-C₅ alkynyl, 3-6-membered cycloalkyl,6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either ofX^(A) and X^(B) are independently C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₅alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 memberedheterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 memberedheteroaryl, each of X^(A) and X^(B) is independently optionallysubstituted by Y¹, wherein Y¹ is selected from: (a) C₁-C₆ alkyloptionally substituted by T¹, wherein T¹ is selected from the groupconsisting of OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11membered heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10membered heteroaryl, —O—(C₁-C₆ alkyl), C(O)OH, oxetan-3-ylmethyl,—C(O)O—(C₁-C₆ alkyl), —S—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl),—NR^(a)R^(b), —N(+)R^(a)R^(b)R^(c) wherein R^(c) is methyl,—C(O)NR^(a)R^(b), —(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl,and phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, and phenyl of T¹ is optionallysubstituted by OH, —C(O)O—(C₁-C₆ alkyl), C₁-C₆ alkyl, halo, CN, oxo,—(C₁-C₆ alkyl)CONR^(a)R^(b), —NR^(a)R^(b), phenyl, or —O—(C₁-C₆ alkyl)optionally substituted by OH; (b) 3-11 membered heterocycloalkyl,—(C₁-C₆ alkylene)-3-11 membered heterocycloalkyl, —C(O)-3-11 memberedheterocycloalkyl, —(C₁-C₆ alkylene)C(O)-3-11 membered heterocycloalkyl,or —OC(O)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl isoptionally substituted by OH, halo, CN, C₁-C₆ alkyl, —(C₁-C₆alkylene)-CF₃, oxo, —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl),—C(O)O—(C₁-C₆ alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl), —C(O)NR^(a)R^(b),—NR^(a)R^(b), —(C₁-C₆ alkylene)-phenyl, or —C(O)-4-6 memberedheterocycloalkyl optionally substituted by —NR^(a)R^(b); (c) N(+)(AA)₃,wherein each AA is independently C₁-C₆ alkyl optionally substituted byphenyl; (d) 3-6 membered cycloalkyl optionally substituted by OH, halo,NR^(a)R^(b), or CN; (e) CN, halo, or oxo; (f) —C(O)—(C₁-C₆ alkyl),—C(O)OH, —C(O)O—(C₁-C₆ alkylene)-phenyl, —SO₂—(C₁-C₆ alkyl),—C(O)NR^(a)R^(b), or —C(O)-4-6 membered heterocycloalkyl optionallysubstituted by —(C₁-C₆ alkyl) or —NR^(a)R^(b), or —C(O)O—(C₁-C₆ alkyl)optionally substituted by OH, NR^(a)R^(b), or 3-11 memberedheterocycloalkyl wherein said heterocycloalkyl is optionally substitutedby C₁-C₆ alkyl; (g) OH, —O-phenyl, or —O—(C₁-C₆ alkyl), wherein thealkyl is optionally substituted by OH or —NR^(a)R^(b); (h) phenyloptionally substituted by OH, halo, C₁-C₆ alkyl, CF₃, or CN; (i) 5-6membered heteroaryl optionally substituted by OH, halo, C₁-C₆ alkyl,CF₃, CN, or 3-11 membered heterocycloalkyl optinally substituted byC₁-C₆ alkyl or 3-11 membered heterocycloalkyl; (j) isoindolin-2-yloptionally substituted by halo; (k) —NR^(a)R^(b), and (l)—O—CH₂C(O)-3-11 membered heterocycloalkyl; wherein R^(a) and R^(b) areindependently selected from: (a) H, (b) C₁-C₆ alkyl optionallysubstituted by OH, halo, CN, —C(O)OH, —C(O)O—(C₁-C₆alkyl), —C(O)O-(3-11membered heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl),—S—(C₁-C₆ alkyl), naphthylenyl, —NR^(az)R^(bz), —C(O)NR^(az)R^(bz), oxo,—O—(C₁-C₆ alkyl), 5-6 membered heteroaryl optionally substituted byC₁-C₆ alkyl or halo, or benzo[1,3]dioxol-2-yl, or 3-11 memberedheterocycloalkenyl optionally substituted by oxo; (c) —(C₁-C₆alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionallysubstituted by OH, halo, or CN; (d) —(C₁-C₆ alkylene)-phenyl whereinalkylene is optionally substituted by halo and the phenyl is optionallysubstituted by OH, halo, CF₃, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆alkyl, or —O-phenyl; (e) —(C₁-C₆ alkylene)-4-6 membered heterocycloalkylwherein the heterocycloalkyl is optionally substituted by halo, oxo, orC₁-C₆ alkyl; (f) —(C₁-C₆ alkylene)-O-phenyl wherein the phenyl isoptionally substituted by halo, C₁-C₆ alkyl, or —O-phenyl; (g) —(C₁-C₆alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, orC₁-C₆ alkyl optionally substituted by OH or CN; (h) C₂-C₅ alkenyl; (i)4-6 membered heterocycloalkyl optionally substituted by halo, (j)—(C₁-C₆ alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,(k) phenyl, (l) —C(O)(C₁-C₆ alkyl), (m) —C(O)O(C₁-C₆ alkyl), (n)—C(O)O(3-6 membered cycloalkyl), and (o) —C(O)-phenyl, wherein R^(az)and R^(bz) are each independently selected from (a) H, (b) C₁-C₆ alkyloptionally substituted by OH, halo, CN, —C(O)OH, —C(O)O—(C₁-C₆alkyl),—C(O)O-(3-11 membered heterocycloalkyl), —C(O)O—(C₁-C₆ alkyl)-S—(C₁-C₆alkyl), —S—(C₁-C₆ alkyl), naphthylenyl, -oxo, —O—(C₁-C₆ alkyl), 5-6membered heteroaryl optionally substituted by C₁-C₆ alkyl or halo, orbenzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionallysubstituted by oxo; (c) —(C₁-C₆ alkylene)-3-6 membered cycloalkylwherein the alkylene is optionally substituted by OH, halo, or CN; (d)—(C₁-C₆ alkylene)-phenyl wherein alkylene is optionally substituted byhalo and the phenyl is optionally substituted by OH, halo, CF₃, C₁-C₆alkyl, —O—(C₁-C₆ alkyl), —S—(C₁-C₆ alkyl, or —O-phenyl; (e) —(C₁-C₆alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl isoptionally substituted by halo, oxo, or C₁-C₆ alkyl; (f) —(C₁-C₆alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo,C₁-C₆ alkyl, or —O-phenyl; (g) —(C₁-C₆ alkyl)3-6 membered cycloalkyloptionally substituted by OH, halo, CN, or C₁-C₆ alkyl optionallysubstituted by OH or CN; (h) C₂-C₅ alkenyl; (i) 4-6 memberedheterocycloalkyl optionally substituted by halo, (j) —(C₁-C₆alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl, (k)phenyl, (l) —C(O)(C₁-C₆ alkyl), (m) —C(O)O(C₁-C₆ alkyl), (n) —C(O)O(3-6membered cycloalkyl), and (o) —C(O)-phenyl, with the following provisos:when R⁰, R⁰⁰, and R⁰¹ are each H and Ring Q is

where t¹ is 0, then X^(A) is not methyl, 2-methylpropan-2-ol, ortetrahydropyranyl.
 2. The compound of claim 1, further defined as acompound of Formula (II):

wherein: w is 0 or 1; R^(0b) is H or NH₂; R^(1b) is selected from thegroup consisting of a. H, b. C₁-C₆ alkyl optionally substituted by OH,halo, CN, —O—(C₁-C₆ alkyl), naphthylenyl, 5-6 membered heteroaryl, or—C(O)NR^(v)R^(w), wherein R^(v) and R^(w) are independently H or C₁-C₆alkyl optionally substituted by halo, c. —(C₁-C₆ alkylene)-3-6 memberedcycloalkyl wherein the cycloalkyl is optionally substituted by CN, d.—(C₁-C₆ alkylene)-phenyl wherein the alkyl is optionally substituted byhalo and wherein the phenyl is optionally substituted by OH, halo, CF₃,C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) or —O-phenyl, e. —(C₁-C₆ alkylene)-4-6membered heterocycloalkyl wherein the heterocycloalkyl is optionallysubstituted by halo or C₁-C₆ alkyl, f. —(C₁-C₆ alkylene)-O-phenylwherein the phenyl is optionally substituted by halo or C₁-C₆ alkyl, org. 3-6 membered cycloalkyl; R^(2b) is selected from the group consistingof H, C₁-C₆ alkyl optionally substituted by halo, or C₂-C₅ alkenyl; orR^(1b) and R^(2b) together form a 3-11 membered heterocycloalkyloptionally substituted by OH; R^(3b) is absent or methyl, wherein whenR^(3b) is methyl, the nitrogen to which it is attached is N+ and w is 1;R^(4b) is a bond or C₁-C₆ alkylene; R^(5b) is selected from the groupconsisting of H, OH, and phenyl; and Ring F is a 3-7 memberedheterocycloalkyl wherein p^(1b) is 0, 1 or 2 and p^(2b) is 0, 1 or 2;wherein w is equal to 1 only when R^(3b) is methyl.
 3. The compound ofclaim 1, further defined as a compound of Formula (Ia) or Formula (Ib):

wherein: R^(0a) is H or NH₂; R^(1a) is bound to a nitrogen atom of RingA in (Ia) or is bound to a carbon atom of Ring B in (Ib), and isselected from the group consisting of: a. H, b. C₁-C₆ alkyl optionallysubstituted by OH, halo, —O—(C₁-C₆ alkyl), —SO₂—(C₁-C₆ alkyl),-(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, —OC(O)-4-6membered heterocycloalkyl, or phenyl; c. —(C₁-C₆ alkylene)-O—(C₁-C₆alkylene)-phenyl wherein the phenyl is optionally substituted by halo;d. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl isoptionally substituted by halo, OH, or CN; e. —(C₁-C₆ alkylene)-4-6membered heterocycloalkyl, wherein the heterocycloalkyl is optionallysubstituted by oxo, C₁-C₆ alkyl, —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆alkyl), —SO₂—(C₁-C₆ alkyl), —C(O)-4-6 membered heterocycloalkyl, or—C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl); f. —C(O)O—(C₁-C₆ alkylene)-OH; and g.—C(O)O—(C₁-C₆ alkylene)-phenyl; h. —NR^(a)R^(b), wherein R^(a) and R^(b)are independently selected from the group consisting of H and C₁-C₆alkyl optionally substituted by OH, halo, CN, phenyl, and 3-7 memberedheterocycloalkyl; R^(2a) is selected from the group consisting of H,C₁-C₆ alkyl optionally substituted by OH, and phenyl; R^(3a) is selectedfrom the group consisting of H, C₁-C₆ alkyl optionally substituted byOH, and phenyl; Ring A is a 3-7 membered heterocycloalkyl; and Ring B isa 3-7 membered heterocycloalkyl or a 3-7 membered heterocyclyalkenyl,wherein p^(1a) is 0, 1 or 2 and p^(2a) is 0, 1 or 2, provided that RingA and Ring B together form a 6-11 membered bicyclic heterocycloalkyl. 4.The compound of claim 1, further defined as a compound of Formula (III):

wherein: ROC is H or NH₂; R³ is (i) or (ii): (i)

wherein: R^(1c) is selected from the group consisting of H, C₁-C₆ alkyl,—(C₁-C₆ alkyl)-phenyl, —C(O)—(C₁-C₆ alkyl), —C(O)-phenyl, and 4-6membered heterocycloalkyl; R^(2c) is H or C₁-C₆ alkyl; and R^(3c) is abond or C₁-C₆ alkylene optionally substituted by oxo; or R^(1c) andR^(2c) together form a 3-11 membered heterocycloalkyl optionallysubstituted by C₁-C₆ alkyl, oxo, or —(C₁-C₆ alkylene)-phenyl; or R^(1c)and R^(3c) together form a 3-7 membered heterocycloalkyl; (ii) H; C₁-C₆alkyl optionally substituted by OH, —SO₂—(C₁-C₆ alkyl), phenyl, or—O—(C₁-C₆ alkylene)-phenyl; —(C₁-C₆ alkylene)-C(O)O(C₁-C₆ alkyl); or 4-6membered heterocycloalkyl optionally substituted by —C(O)(C₁-C₆ alkyl);and Ring G is a 3-7 membered heterocycloalkyl wherein p^(1c) is 0, 1 or2 and p^(2c) is 0, 1 or
 2. 5. The compound of claim 1, further definedas a compound of Formula (IV):

wherein: R^(Od) is H or NH₂; R^(1d) is 3-11 membered heterocycloalkyl or—C(O)-3-11 membered heterocycloalkyl, wherein the heterocycloalkyl isoptionally substituted C₁-C₆ alkyl, CF₃, or fluoro, or R^(1d) is —(C₁-C₆alkylene)-NR^(v)R^(w), wherein R^(v) and R^(w) are independently H orC₁-C₆ alkyl optionally substituted by halo.
 6. The compound of claim 1,further defined as a compound of Formula (V):

wherein: R^(0e) is H or NH₂; R^(1e) is selected from the groupconsisting of a. H, b. C₁-C₆ alkyl optionally substituted by halo, CN,or phenyl, c. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein thecycloalkyl is optionally substituted by CN, d. —(C₁-C₆ alkylene)-4-6membered heterocycloalkyl wherein the heterocycloalkyl is optionallysubstituted by C₁-C₆ alkyl; R^(2e) is H or C₁-C₆ alkyl; or R^(1e) andR^(2e) together form a 3-11 membered heterocycloalkyl optionallysubstituted by halo or —NR^(v)R^(w), wherein R^(v) and R^(w) areindependently H or C₁-C₆ alkyl optionally substituted by halo; R^(3e) isa bond or C₁-C₆ alkylene optionally substituted by oxo; and Ring H is a3-7 membered heterocycloalkyl wherein p^(1e) is 0, 1 or 2 and p^(2e) is0, 1 or
 2. 7. The compound of claim 1, further defined as a compound ofFormula (VI):

wherein: R^(0f) is H or NH₂; R^(1f) is selected from the groupconsisting of C₁-C₆ alkyl optionally substituted by halo, 3-6 memberedcycloalkyl, or phenyl; and Ring J is a 6-7 membered heterocycloalkylwherein p^(1f) is 1 or 2 and p^(2f) is 1 or
 2. 8. The compound of claim1, further defined as a compound of Formula (VII):

wherein: R^(0g) is H or NH2; R^(1g) is selected from the groupconsisting of C₁-C₆ alkyl; R^(2g) is selected from the group consistingof C₁-C₆ alkyl.
 9. The compound of claim 1, further defined as acompound of Formula (VIII):

wherein: R^(0h) is H or NH₂; R^(1h) is selected from the groupconsisting of H and C₁-C₆ alkyl optionally substituted by CN, 3-6membered cycloalkyl, or 4-6 membered heterocycloalkylene-C(O)O—(C₁-C₆alkylene)-phenyl; Ring C is 3-7 membered cycloalkyl or 3-7 memberedheterocycloalkyl; and Ring D is a 3-7 membered heterocycloalkylsubstituted at the sole nitrogen by R^(1h); and provided Rings C and Dtogether form a 3-11 membered spiro heterocycloalkyl.
 10. The compoundof claim 1, further defined as a compound of Formula (IX):

wherein: R^(0j) is H or NH₂; R^(3j) is selected from the groupconsisting of H and C₁-C₆ alkyl optionally substituted by OH, 3-6membered cycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —SO₂—(C1-C₆alkyl) and phenyl, wherein the phenyl is optionally substituted by CN;R^(4j) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by OH; or R^(3j) and R^(4j) together form a4-6-membered heterocycloalkyl; R^(5j) is selected from the groupconsisting of H and C₁-C₆ alkyl; and Ring K is a 6-7 memberedheterocycloalkyl wherein p^(1j) is 1 or 2 and p²j is 1 or
 2. 11. Thecompound of claim 1, further defined as a compound of Formula (X):

wherein: R^(0k) is H or NH₂; R^(1k) is selected from the groupconsisting of a. H, b. C₁-C₆ alkyl optionally substituted by halo, CN,or phenyl, c. —(C₁-C₆ alkylene)-3-6 membered cycloalkyl wherein thecycloalkyl is optionally substituted by CN, d. —(C₁-C₆ alkylene)-4-6membered heterocycloalkyl wherein the heterocycloalkyl is optionallysubstituted by C₁-C₆ alkyl; R^(2k) is selected from the group consistingof H and C₁-C₆ alkyl; or R^(1k) and R^(2k) together form a 3-11 memberedheterocycloalkyl optionally substituted by halo; C₁-C₆ alkyl optionallysubstituted by OH; or —NR^(v)R^(w), wherein R^(v) and R^(w) areindependently H or C₁-C₆ alkyl optionally substituted by halo; andR^(3k) is a bond, methylene, or —C(═O)—.
 12. The compound of claim 1,wherein X^(A) and X^(B) are independently selected from the groupconsisting of 3-6-membered cycloalkyl, 6-10 membered aryl, 5-6 memberedheterocycloalkenyl, and 5-10 membered heteroaryl, wherein each of X^(A)and X^(B) are independently optionally substituted by Y¹.
 13. Thecompound of claim 1, wherein either X^(A) or X^(B) is a 3-11 memberedheterocycloalkyl optionally substituted by Y¹.
 14. The compound of claim1, wherein Ring Q is (i).
 15. The compound of claim 1, wherein t¹ is 0.16. The compound of claim 1, wherein t¹ is
 1. 17. The compound of claim1, wherein Ring Q is (ii).
 18. The compound of claim 1, wherein t² is 0.19. The compound of claim 1, wherein t² is
 1. 20. The compound of claim1, wherein R⁰, R⁰⁰ and R⁰¹ are each H.
 21. The compound of claim 1,wherein R⁰ is NH₂.
 22. The compound of claim 1, wherein Ring Q is (i),t¹ is 0 or 1, and R⁰, R⁰⁰ and R⁰¹ are each H.
 23. The compound of claim1, wherein Ring Q is (i), t¹ is 1, and X^(A) is NR^(a)R^(b), whereinR^(a) and R^(b) are each independently H, C₁-C₆ alkyl optionallysubstituted with 5-6 membered heteroaryl, or 3-6 membered cycloalkyloptionally substituted by OH, halo, CN, or C₁-C₆ alkyl optionallysubstituted by OH.
 24. The compound of claim 1, wherein Ring Q is (i),t¹ is 0, and X^(A) is C₁-C₆ alkyl or 3-6 membered cycloalkyl, whereinX^(A) is optionally substituted by —NR^(a)R^(b), wherein R^(a) and R^(b)are independently H or C₁-C₆ alkyl.
 25. The compound of claim 1,selected from Table
 1. 26. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier, diluentor excipient.
 27. A method of preventing, treating or lessening theseverity of a disease or condition responsive to the inhibition of aJanus kinase activity in a patient, comprising administering to thepatient a therapeutically effective amount of a compound of claim
 1. 28.The method of claim 27, wherein the disease or condition is asthma. 29.The method of claim 27, wherein the Janus kinase is JAK1.